Pharmaceutically active pyrrolidine derivatives

ABSTRACT

The present invention is related to pyrrolidine derivatives of formula I. Said compounds are preferably for use as pharmaceutically active compounds. Specifically, pyrrolidine derivatives of formula I are useful in the treatment and/or prevention of premature labor, premature birth and dysmenorrhea. In particular, the present invention is related to pyrrolidine derivatives displaying a substantial modulatory, notably an antagonist activity of the oxytocin receptor. More preferably, said compounds are useful in the treatment and/or prevention of disease states mediated by oxytocin, including premature labor, premature birth and dysmenorrhea. The present invention is furthermore related to novel pyrrolidine derivatives as well as to methods of their preparation. 
     
       
         
         
             
             
         
       
     
     wherein X is selected from the group consisting of CR 6 R 7 , NOR 6 , NNR 6 R 7 ;
 
A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO 2 —, —SO 2 NH—, —CH 2 —,
 
B is either a group —C═O)—NR 8 R 9  or represents a heterocyclic residue having the formula wherein Q is NR 10 , O or S; n is an integer selected of 0, 1 or 2;
 
     
       
         
         
             
             
         
       
     
     Y, Z and E form together with the 2 carbons to which they are attached a 5-6 membered aryl or heteroaryl ring.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 10/239,912, filed Feb. 10,2003, which is a 371 national stage application of PCT/EP01/03171, filedMar. 20, 2001. The entire contents of both applications beingincorporated herein by reference.

FIELD OF THE INVENTION

The present invention is related to pyrrolidine derivatives. Saidcompounds are preferably for use as pharmaceutically active compounds.Specifically, pyrrolidine derivatives of formula I are useful in thetreatment and/or prevention of premature labor, premature birth anddysmenorrhea. In particular, the present invention is related topyrrolidine derivatives displaying a substantial modulatory, notably anantagonist activity of the oxytocin receptor. More preferably, saidcompounds are useful in the treatment and/or prevention of diseasestates mediated by oxytocin, including premature labor, premature birthand dysmenorrhea. The present invention is furthermore related to novelpyrrolidine derivatives as well as to methods of their preparation.

BACKGROUND OF THE INVENTION

Oxytocin (OT) is a peptide hormone and causes the contraction of theuterus of mammals during labor. The corresponding Oxytocin receptorbelongs to the family of G-protein-coupled receptors and is similar toV_(1a) and V₂ vasopressin receptors. OT receptors increase dramaticallyduring the course of pregnancy. The concentration of OT receptors hasbeen shown to correlate with spontaneous uterine activity (M. Maggi etal. J. Clin. Endocrinol Metabol; 70; 1142, 1990). Premature labor,though, and premature birth is undesired as it represents a major causeof perinatal morbidity and mortality. Hence, the management of pretermlabor represents a significant problem in the field of obstetrics.

In recent years, strong evidence has accumulated indicating that thehormone oxytocin plays a major role in initiating labor in mammals,notably in humans. Thereby, it is assumed that oxytocin exerts saideffect in a direct as well as an indirect way, by contracting theuterine myometrium and by enhancing the synthesis and release ofcontractile prostaglandins from the uterine endometrium/decidua. Theseprostaglandins may furthermore play a role in the cervical ripeningprocess. This “up-regulation” of oxytocin receptors and increaseduterine sensitivity seems to be due to trophic effects of rising plasmalevels of estrogen towards term. By down-regulating oxytocin, it isexpected that both the direct (contractile) and indirect (increasedprostaglandin synthesis) effects of oxytocin on the uterine could beblocked. An oxytocin modulator, e.g. blocker or antagonists would likelybe more efficacious for treating preterm labor than current regimens.Moreover, as oxytocin at term has only an effect on the uterus, such anoxytocin modulator would have only few or no side effect.

A further condition being related to oxytocin is dysmenorrhea, which ischaracterised by cyclic pain associated with menses during ovulatorycycles. Said pain is believed to result from uterine contractions andischemia, probably mediated by the effect of prostaglandins produced inthe secretory endometrium. By blocking both the indirect and directeffects of oxytocin on the uterus, an oxytocin antagonist is believedmore efficacious for treating dysmenorrhea than current regimens.

Some agents counteracting the action of Oxytocin (OT) are currently usedin clinical studies. Such tocolytic agents (i.e. uterine-relaxingagents) include beta-2-adrenergic agonists, magnesium sulfate andethanol. The leading beta-2-adrenergic agonists is Ritodrine, whichcauses a number of cardiovascular and metabolic side effects, includingtachycardia, increased renin secretion, hyperglycemia and reactivehypoglycemia in the infant. Further beta-32-adrenergic agonists,including terbutaline and albuterol have side effects similar to thoseof ritodrine. Magnesium sulfate at plasma concentrations above thetherapeutic range of 4 to 8 mg/dL can cause inhibition of cardiacconduction and neuromuscular transmission, respiratory depression andcardiac arrest, thus making this agent unsuitable when renal function isimpaired. Ethanol is as effective as ritodrine in preventing prematurelabor, but it does not produce a corresponding reduction in theincidence of fetal respiratory distress that administration of ritodrinedoes.

The principal drawback to the use of peptide antagonists including alsoatosiban is the problem of low oral bioavailability resulting fromintestinal degradation. Hence, they must be administered parenterally.

The development of non-peptide ligands for peptide hormone receptors areexpected to overcome this problem. The first to report small moleculeselective oxytocin antagonists was Merck. Apart from cyclichexapeptides, Merck suggested indanylpiperidines and tolylpiperazines asorally deliverable OT antagonists (Evans et al. J. Med. Chem., 35, 3919(1992). In WO 96/22775 and U.S. Pat. No. 5,756,497 Merck reportedbenzoxazinylpiperidines or benzoxazinones as OT receptor antagonists.

It is a purpose of this invention to provide substances which moreeffectively down-regulate—up to antagonizing—the function of OT indisease states in animals, preferably mammals, especially in humans. Itis another purpose of this invention to provide a method of antagonizingthe functions of oxytocin in disease states of mammals. It is also anobjective of the present invention to provide small molecule chemicalcompounds for the modulation, preferably the down-regulation or evenantagonisation of the Oxytocin receptor. Moreover, it is an objective ofthe present invention to provide methods for preparing said smallmolecule chemical compounds. It is furthermore an objective of thepresent invention to provide a new category of pharmaceuticalformulations for the treatment of preterm labor and dysmenorrhea, and/ordiseases mediated by the Oxytocin receptor. It is finally an objectiveof the present invention to provide a method of treating or preventdisorders mediated by the Oxytocin receptor, like preterm labor anddysmenorrhea by antagonising the binding of Oxytocin to its receptor.

DESCRIPTION OF THE INVENTION

The aforementioned objectives have been met according to the independentclaims. Preferred embodiments are set out within the dependent claimswhich are incorporated herewith.

The following paragraphs provide definitions of the various chemicalmoieties that make up the compounds according to the invention and areintended to apply uniformly through-out the specification and claimsunless an otherwise expressly set out definition provides a broaderdefinition.

“C₁-C₆-alkyl” refers to monovalent alkyl groups having 1 to 6 carbonatoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and thelike.

“Aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to14 carbon atoms having a single ring (e.g. phenyl) or multiple condensedrings (e.g. naphthyl). Preferred aryl include phenyl, naphthyl,phenantrenyl and the like.

“C₁-C₆-alkyl aryl” refers to C₁-C₆-alkyl groups having an arylsubstituent, including benzyl, phenethyl and the like.

“Heteroaryl” refers to a monocyclic heteromatic, or a bicyclic or atricyclic fused-ring heteroaromatic group. Particular examples ofheteroaromatic groups include optionally substituted pyridyl, pyrrolyl,furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl,isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl,imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl,quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,5,6,7,8-tetrehydroisoquinolyl, purinyl, pteridinyl, carbazolyl,xanthenyl or benzoquinolyl.

“C₁-C₆-alkyl heteroaryl” refers to C₁-C₆-alkyl groups having aheteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl,2-(1H-indol-3-yl)ethyl and the like.

“Alkenyl” refers to alkenyl groups preferably having from 2 to 6 carbonatoms and having at least 1 or 2 sites of alkenyl unsaturation.Preferable alkenyl groups include ethenyl (—CH═CH₂), n-2-propenyl(allyl, —CH₂CH═CH₂) and the like.

“Alkynyl” refers to alkynyl groups preferably having from 2 to 6 carbonatoms and having at least 1-2 sites of alkynyl unsaturation, preferredalkynyl groups include ethynyl (—C≡CH), propargyl (—CH₂C≡CH), and thelike.

“Acyl” refers to the group —C(O)R where R includes “C₁-C₆-alkyl”,“aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”.

“Acyloxy” refers to the group —OC(O)R where R includes “C₁-C₆-alkyl”,“aryl”, “hetero-aryl”, “C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”.

“Alkoxy” refers to the group —O—R where R includes “C₁-C₆-alkyl” or“aryl” or “heteroaryl” or “C₁-C₆-alkyl aryl” or “C₁-C₆-alkylheteroaryl”. Preferred alkoxy groups include by way of example, methoxy,ethoxy, phenoxy and the like.

“Alkoxycarbonyl” refers to the group —C(O)OR where R includes“C₁-C₆-alkyl” or “aryl” or “heteroaryl” or “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”.

“Aminocarbonyl” refers to the group —C(O)NRR′ where each R, R′ includesindependently hydrogen or C₁-C₆-alkyl or aryl or heteroaryl or“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl hetero-aryl”.

“Acylamino” refers to the group —NR(CO)R′ where each R, R′ isindependently hydrogen or “C₁-C₆-alkyl” or “aryl” or “heteroaryl” or“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”.

“Halogen” refers to fluoro, chloro, bromo and iodo atoms.

“Sulfonyl” refers to group “—SO₂—R” wherein R is selected from H,“aryl”, “heteroaryl”, “C₁-C₆-alkyl”, “C₁-C₆-alkyl” substituted withhalogens e.g. an —SO₂—CF₃ group, “C₁-C₆-alkyl aryl” or “C₁-C₆-alkylheteroaryl”.

“Sulfoxy” refers to a group “—S(O)—R” wherein R is selected from H,“C₁-C₆-alkyl”, “C₁-C₆-alkyl” substituted with halogens e.g. an —SO—CF₃group, “aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or “C₁-C₆-alkylheteroaryl”.

“Thioalkoxy” refers to groups —S—R where R includes “C₁-C₆-alkyl” or“aryl” or “heteroaryl” or “C₁-C₆-alkyl aryl” or “C₁-C₆-alkylheteroaryl”. Preferred thioalkoxy groups include thiomethoxy,thioethoxy, and the like.

“Substituted or unsubstituted”: Unless otherwise constrained by thedefinition of the individual substituent, the above set out groups, like“alkyl”, “alkenyl”, “alkynyl”, “aryl” and “heteroaryl” etc. groups canoptionally be substituted with from 1 to 5 substituents selected fromthe group consisting of “C₁-C₆-alkyl”, “C₁-C₆-alkyl aryl”, “C₁-C₆-alkylheteroaryl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, primary, secondary ortertiary amino groups or quaternary ammonium moieties, “acyl”,“acyloxy”, “acylamino”, “aminocarbonyl”, “alkoxycarbonyl”, “aryl”,“heteroaryl”, carboxyl, cyano, halogen, hydroxy, mercapto, nitro,sulfoxy, sulfonyl, alkoxy, thioalkoxy, trihalomethyl and the like.Alternatively said substitution could also comprise situations whereneighboring substituents have undergone ring closure, notably whenviccinal functional substituents are involved, thus forming e.g.lactams, lactons, cyclic anhydrides, but also acetals, thioacetals,animals formed by ring closure for instance in an effort to obtain aprotective group.

“Pharmaceutically acceptable salts or complexes” refers to salts orcomplexes of the below-identified compounds of formula I that retain thedesired biological activity. Examples of such salts include, but are notrestricted to acid addition salts formed with inorganic acids (e.g.hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), and salts formed with organic acids such asacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid,pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid,naphthalene disulfonic acid, and polygalacturonic acid. Said compoundscan also be administered as pharmaceutically acceptable quaternary saltsknown by a person skilled in the art, which specifically include thequartenary ammonium salt of the formula —NR, R′, R″⁺Z⁻, wherein R, R′,R″ is independently hydrogen, alkyl, or benzyl, and Z is a counterion,including chloride, bromide, iodide, —O-alkyl, toluenesulfonate,methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate,succinate, acetate, glycolate, maleate, malate, fumarate, citrate,tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).

“Pharmaceutically active derivative” refers to any compound that uponadministration to the recipient, is capable of providing directly orindirectly, the activity disclosed herein.

“Enantiomeric excess” (ee) refers to the products that are obtained byan asymmetric synthesis, i.e. a synthesis involving non-racemic startingmaterials and/or reagents or a synthesis comprising at least oneenantioselective step, whereby a surplus of one enantiomer in the orderof at least about 52% ee is yielded. In the absence of an asymmetricsynthesis, racemic products are usually obtained that do however alsohave the inventive set out activity as OT-R antagonists.

Quite surprisingly, it was now found that pyrrolidine derivativesaccording to formula I are suitable pharmaceutically active agents, byeffectively modulating, in particular by effectively inhibiting the OT-Rfunction and more specifically by antagonising the oxytocin receptor.When the oxytocin receptor is bound by the compounds according toformula I, oxytocin is antagonised by being blocked from its receptorand is therefore unable to exert its biologic or pharmacologicaleffects. The compounds of the present invention are therefore inparticular useful in the treatment and/or prevention of oxytocin-relateddisorders of mammals and in particular of humans. These disordersmediated by the oxytocin receptor, are primarily preterm labor anddysmenorrhea.

The compounds according to the present invention are those of formula I.

Said formula also comprises its geometrical isomers, its opticallyactive forms as enantiomers, diastereomers and its racemate forms, aswell as pharmaceutically acceptable salts thereof. Preferredpharmaceutically acceptable salts of the compound I, are acid additionsalts formed with pharmaceutically acceptable acids like hydrochloride,hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate,acetate, benzoate, succinate, fumarate, maleate, lactate, citrate,tartrate, gluconate, methanesulfonate, benzenesulfonate, andpara-toluenesulfonate salts.

In said formula I, X is selected from the group consisting of CR⁶R⁷,NOR⁶, NNR⁶R⁷.

A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—,—(C═O)—NH—, —(C═S)—NH, —SO₂—, —SO₂NH—, —CH₂—.

B is either an amido group of the formula —(C═O)—NR⁸R⁹ or B represents aheterocyclic residue having the formula B

wherein Q is NR¹⁰, O or S; n is an integer selected of 0, 1 or 2,preferably 0. m is an integer selected of 0, 1, 2 or 3, preferably 0 or1.

Y, Z and E form together with the 2 carbons to which they are attached a5-6 membered aryl or heteroaryl ring.

R¹ is selected from the group comprising or consisting of unsubstitutedor substituted C₁-C₆-alkyl, unsubstituted or substituted C₂-C₆-alkenyl,unsubstituted or substituted C₂-C₆-alkynyl, unsubstituted or substitutedaryl, unsubstituted or substituted heteroaryl, unsubstituted orsubstituted saturated or unsaturated 3-8-membered cycloalkyl, acyl,unsubstituted or substituted C₁-C₆-alkyl aryl, unsubstituted orsubstituted C₁-C₆-alkyl heteroaryl, said cycloalkyl or aryl orheteroaryl groups may be fused with 1-2 further cycloalkyl or aryl orheteroaryl group.

R², R³, R⁴ and R⁵ are independently selected from each other from thegroup consisting of hydrogen, halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy,preferably they are all hydrogen.

R⁶ and R⁷ are independently selected from the group comprising orconsisting of hydrogen, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or substitutedC₂-C₆ alkynyl, unsubstituted or substituted alkoxy, unsubstituted orsubstituted thioalkoxy, halogen, cyano, nitro, acyl, alkoxycarbonyl,aminocarbonyl, unsubstituted or substituted saturated or unsaturated3-8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected ofN, O, S, unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted C₁-C₆-alkyl aryl, unsubstitutedor substituted C₁-C₆-alkyl heteroaryl.

R⁸, R⁹ and R¹⁰ are independently selected from the group comprising orconsisting of hydrogen, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or substitutedC₂-C₆ alkynyl, unsubstituted or substituted saturated or unsaturated3-8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected ofN, O, S, unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl.

Alternatively, each pair R⁶, R⁷ and/or R⁸, R⁹ could form together withthe N atom to which they are attached a 3-8 membered substituted orunsubstituted, saturated or unsaturated heterocyclic ring which maycontain 1-2 further heteroatoms selected from N, S and O and which isoptionally fused with an aryl, heteroaryl or 3-8 membered saturated orunsaturated cycloalkyl ring.

R¹¹ is selected from the group comprising or consisting of hydrogen,unsubstituted or substituted C₁-C₆-alkyl, unsubstituted or substitutedalkenyl, unsubstituted or substituted alkynyl, hydroxy, mercapto,alkoxy, thioalkoxy, aryl, heteroaryl, halogen, nitro, cyano, acyl,acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, sulfonyl, sulfoxy,carboxyl, primary, secondary or tertiary amino groups or quaternaryammonium moieties, unsubstituted or substituted saturated or unsaturated3-8-membered cycloalkyl.

Preferred pyrrolidine derivatives are those compounds according toformula I wherein B is a group —(C═O)—NHR⁹, in which R⁹ is selected fromthe group consisting of unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted alkenyl, unsubstituted or substitutedalkynyl, unsubstituted or substituted saturated or unsaturated3-6-membered cycloalkyl which optionally contains a N atom,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted C₁-C₂-alkyl aryl, unsubstitutedor substituted C₁-C₂-alkyl heteroaryl.

Preferred heteroaryls are pyridyl, pyrrolyl, furyl, thienyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl,benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl,benzotriazolyl, isobenzo-thienyl, 2,1,3-benzothiadiazolyl,2,1,3-benzoxadiazolyl, benzodioxolyl, indolyl, isoindolyl, 3H-indolyl,benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl,quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl,napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl,pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl,5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl,pteridinyl, carbazolyl, xanthenyl, acridinyl or benzoquinolyl andwhereby said heteroaryl could be fused with a 3-8-membered cycloalkylcontaining optionally 1-3 heteroatoms selected from N, O, S.

According to a further preferred embodiment the pyrrolidine derivativesaccording to the present invention carry a residue B¹ which is a fusedheterocycle of the formula

Particularly preferred pyrrolidine derivatives are those compoundsaccording to formula I wherein X is NOR⁶, and R⁶ is selected from thegroup consisting of H, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or substitutedC₂-C₆ alkynyl, unsubstituted or substituted acyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted saturated or unsaturated 3-8-membered cycloalkyl,unsubstituted or substituted C₁-C₆-alkyl aryl, unsubstituted orsubstituted C₁-C₆-alkyl heteroaryl, said cycloalkyl or aryl orheteroaryl groups may be fused with 1-2 further cycloalkyl or aryl orheteroaryl groups. Particularly preferred R⁶ is H, CH₃, unsubstituted orsubstituted CH₂-phenyl or allyl.

Under no circumstances B could be a group COOR or a group —(C═O)NR(OR),whereby R is H, alkyl or acyl. Such compounds, notably having a groupB=hydroxamic acid are described in WO 99/52868 as being potentinhibitors of metalloproteases.

Further particularly preferred pyrrolidine derivatives are thosecompounds according to formula I wherein X is CHR⁶, and R⁶ is selectedfrom the group consisting of halogen, cyano, unsubstituted orsubstituted C₃-C₆ alkyl, unsubstituted or substituted C₂-C₆ alkenyl,unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or substitutedalkoxy, unsubstituted or substituted thioalkoxy, nitro, acyl,alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl, unsubstituted or substitutedsaturated or unsaturated 3-8-membered cycloalkyl, unsubstituted orsubstituted C₁-C₆-alkyl aryl, unsubstituted or substituted C₁-C₆-alkylheteroaryl, said cycloalkyl or aryl or heteroaryl groups may be fusedwith 1-2 further cycloalkyl or aryl or heteroaryl groups. Particularlypreferred R⁶ is halogen, cyano, C₁-C₆ alkyl or an unsubstituted orsubstituted phenyl group.

According to a further preferred embodiment the pyrrolidine derivativeshave a substituent A being —(C═O)—, or —(C═O)—NH—, or —SO₂—, mostpreferred is —(C═O)—.

More preferred groups R¹ are substituted or unsubstituted C₁-C₆-alkyl,C₂-C₆-alkenyl, unsubstituted or substituted C₂-C₆-alkynyl, aryl,heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl and stillmore preferred R¹ are C₁-C₆-alkyl or aryl. A particularly preferredsubstituent R′ is biphenyl.

According to a most preferred embodiment, the pyrrolidine derivativesaccording to formula I are those wherein X is ═NOR⁶ or ═CHCl, R⁶ is aC₁-C₆-alkyl, e.g. a methyl group, or aryl or C₁-C₆-alkyl aryl group, Ais —(C═O)— and R¹ is a C₁-C₆-alkyl or aryl or C₁-C₆-alkyl aryl group.Even more preferred are those pyrrolidine derivatives, wherein X is═NOR⁶, or ═CHCl, R⁶ is methyl, B is an amido group of the formula—(C═O)NHR⁹, wherein R⁹ is an unsubstituted or substituted C₁-C₆-alkylaryl group, e.g. a substituted phenylethyl group, A is —(C═O)— and R¹ isa substituted or unsubstituted biphenyl or an acetylmethyl group.

The compounds of formula I may contain one or more asymmetric centersand may therefore exist as enantiomers or diasteroisomers. It is to beunderstood that the invention includes both mixtures and separateindividual isomers or enantiomers of the compounds of formula I. In aparticularly preferred embodiment the pyrrolidine derivatives accordingto formula I are obtained in an enantiomeric excess of at least 52% ee,preferably of at least 92-98% ee. Also E/Z isomers with regard topyrrolidine derivatives having residues X being ═CR⁶R⁷ whereby both R⁶R⁷are different from each other, and/or with regard to pyrrolidinederivatives having residues X being ═NOR⁶ or ═NNR⁶R⁷ are comprised bythe present invention.

Specific examples of compounds of formula I include the following:

-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-methoxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone    O-methyloxime-   (2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxy-imino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(6-quinolinyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-acetoacetyl-N-benzyl-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-furylmethyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(4-chlorophenoxy)acetyl]-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-allyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-(cyanomethylene)-N-(2-furylmethyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-acetyl-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-furylmethyl)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-benzyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-methyl-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-(diphenylacetyl)-4-(ethoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-4-(cyanomethylene)-1-(diphenylacetyl)-2-pyrrolidinecarboxamide-   (3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-(diphenylacetyl)-3-pyrrolidinone    O-methyloxime-   (2S)-2-[1-([1,1′-biphenyl]-4-ylcarbonyl)-4-methylene-2-pyrrolidinyl]-1H-benzimidazole-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-methoxyethyl)-2-pyrrolidinecarboxamide-   (3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-(diphenylacetyl)-3-pyrrolidinone    O-allyloxime-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[2-(diethylamino)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(3,4-dimethoxybenzyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-acetoacetyl-4-(methoxyimino)-N-(1-naphthylmethyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-allyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(diphenylacetyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N¹-pentyl-N²-(6-quinolinyl)-1,2-pyrrolidine-dicarboxamide-   (2S,4EZ)-4-(chloromethylene)-1-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide-   (2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-methylene-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(6-quinolinyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-benzylidene-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1    acetoacetyl-4-(methoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-acetyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N¹-(3,5-dichlorophenyl)-N²-(6-quinolinyl)-1,2-pyrrolidinedicarboxamide-   (2S,4EZ)-4-(methoxyimino)-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-(chloromethylene)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-(diphenylacetyl)-4-(methoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[2-(diethylamino)ethyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-[4-(dimethylamino)butanoyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-4-(methoxy-imino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-benzyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-(ethoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N²-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N¹-(3-methoxyphenyl)-1,2-pyrrolidinedicarboxamide-   (2S,4EZ)-1-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-{[(4-methoxybenzyl)-oxy]imino}-2-pyrrolidinecarboxamide-   (2S)—N-(2-furylmethyl)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-(diphenylacetyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-benzoyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quinolinyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-acetoacetyl-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N²-[(2RS)-2-hydroxy-2-phenethyl]-N¹-pentyl-1,2-pyrrolidinedicarboxamide-   (2S,4EZ)-4-[(benzyloxy)imino]-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide-   (2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-methylene-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(diphenylacetyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-(4-cyanobenzoyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quinolinyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(methoxyacetyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(1,3-benzodioxol-5-ylmethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxy-imino)-2-pyrrolidinecarboxamide-   (3EZ,5S)-5-[(4-acetyl-1-piperazinyl)carbonyl]-1-acryloyl-3-pyrrolidinone    O-(3,4-dichlorobenzyl)oxime-   S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-methylene-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-(cyanomethylene)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-3-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-(4-benzoylbenzoyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-(3-phenoxybenzoyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-(2-phenoxybenzoyl)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-N-methyl-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S,2S,3R,4R)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(trans-4-hydroxycyclohexyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1-hydroxycyclohexyl)methyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1-hydroxycyclohexyl)methyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1-hydroxycyclohexyl)methyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)-propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(2-naphthyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide.-   (2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(3-hydroxypropyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-(3-hydroxypropyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-1-[4-(4-pyridinyl)benzoyl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-1-[4-(3-pyridinyl)benzoyl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-3-pyrrolidinone    O-methyloxime-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-benzyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-benzyl-N-(2-hydroxyethyl)-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-1-[4-(4-pyridinyl)benzoyl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-1-[4-(3-pyridinyl)benzoyl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylsulfonyl)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-3-pyrrolidinone    O-methyloxime-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-anilinoethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-anilinoethyl)-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-1-piperidinyl)carbonyl]-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-([1,1′-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy-1-piperidinyl)carbonyl]-3-pyrrolidinone-   O-methyloxime-   (2S,4EZ)-N-[(1S,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(3-amino-3-oxopropyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(4-hydroxybutyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-(4-hydroxybutyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1R,2S,3R,4S)-3-(hydroxymethyl)bicyclo-[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1R,2S)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4E and    4Z)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4E and    4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4E and    4Z)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1R,2S)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1S,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2RS)-3-({[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-carbonyl}amino)-2-hydroxypropanoic    acid-   (2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1RS)-2-hydroxy-1-methylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   4-({[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-amino)butanoic    acid-   (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(2-naphthyl)ethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1RS)-2-hydroxy-1-methylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (3EZ,5S)-5-[(4-hydroxy-1-piperidinyl)carbonyl]-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-3-pyrrolidinone    O-methyloxime-   (2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-4-(methoxyimino)-1-[(2′-methyl[1′,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-1-[(2′-methyl[1′,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(3-hydroxypropyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-amino-2-oxoethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-amino-2-oxoethyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2R,3S,4R)-3-(hydroxymethyl)-bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1R,2S,3R,4S)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(trans-4-hydroxycyclohexyl)-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-1-[(2′-methyl[1′,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2R,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2R,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′-cyano[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,3-dimethyl[1′,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′-cyano[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(3′,4′-dichloro[,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,3-dimethyl[1′,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-amino-2-oxoethyl)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-amino-2-oxoethyl)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′-cyano[1,1′-biphenyl]-4-yl)carbonyl]-N-[(1R,2R)-2-(hydroxymethyl)-cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (3EZ,5S)-5-(3,4-dihydro-2(1H)-isoquinolinylcarbonyl)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-3-pyrrolidinone    O-methyloxime-   (2S,4EZ)-N-[(1R)-2-hydroxy-1-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(1R,2S)-2-hydroxy-1,2-diphenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2RS)-2-[({(2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1-biphenyl]-4-yl)carbonyl]-pyrrolidinyl}carbonyl)amino]-3-phenylpropanoic    acid-   (2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   4′-{[(2S,4EZ)-2-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-4-(methoxyimino)-pyrrolidinyl]carbonyl}[1,1′-biphenyl]-2-carbonitrile-   (3EZ,5S)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-({4-[4-(trifluoromethyl)phenyl]-1-piperazinyl}carbonyl)-3-pyrrolidinone    O-methyloxime-   (3EZ,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}carbonyl)-3-pyrrolidinone    O-methyloxime-   (2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-(methoxyimino)-N-methyl-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-(methoxyimino)-N,N-dimethyl-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(3R)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(3S)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(3R)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(3S)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-{[2′-(trifluoro-methyl)[1,1′-biphenyl]-4-yl]carbonyl}-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-{[2′-chloro[1,1′-biphenyl]-4-yl]carbonyl}-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-(2-hydroxyphenyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[2-(hydroxymethyl)phenyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4E and    4Z)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-phenylethyl)-2-pyrrolidinecarboxamide

Thereby, the most preferred compounds are those which are selected fromthe group consisting of:

-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone    O-methyloxime-   (2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide-   (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino(,N-(6-quinolinyl)-2-pyrrolidinecarboxamide-   (2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide-   (2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

A further aspect of the present invention is related to the use of thepyrrolidine derivatives according to formula I for the preparation ofpharmaceutical compositions for the treatment and/or prevention ofpremature labor, premature birth, for stopping labor prior to cesareandelivery and dysmenorrhea. Preferably, the compounds according toformula I are suitable for the modulation of the OT function, thusspecifically allowing the treatment and/or prevention of disorders whichare mediated by the oxytocin receptor. Said treatment involves themodulation—notably the down regulation or the antagonisation—of theoxytocin receptor.

More specifically, the compounds of the present invention are useful forthe treatment of preterm labor, premature birth, dysmenorrhea and forstopping labor prior to cesarean delivery.

Still a further aspect of the present invention is related to theactually novel pyrrolidine compounds of formula I. Some very fewcompounds have actually been disclosed prior to the filing of thepresent application, without any medical use though. Said knowncompounds of formula I are those, wherein

X is (═CH₂), A is —(C═O)—O—, R¹ is a t-butyl group and B is —(C═O)—NMe₂(Tetrahedron 53(2), 539, 1997); —(C═O)—NHMe (WO 95/47718);—(C═O)—NH—CH(Me)—(C═O)—NH—CH(Me)—COOH (WO 95/47718); or—(C═O)—NH—CH(COOCH₂-Ph)—CH₂—COOPh (Tetrahedron 48(31), 6529, 1992).

X is (═CHR⁶) with R⁶ being cyclohexylmethyl, A is —(C═O)—O—, R¹ is at-butyl group and is —(C═O)—NH-t-butyl (Biorg. Chem. Lett. 3(8), 1485,1993).

X is C₁-C₂₀ alkylidene, A is —(C═O)—O—, R¹ is a t-butyl and B is

wherein R is C₁-C₁₂ alkyl and Hal is Cl, Br, J. Said compounds aredisclosed in DE-1,932,823 as intermediates.

X is C₁-C₂₀ alkylidene, A-R¹ is a protective group and B is

with R being H or C₁-C₁₂ alkyl (GB-1,118,306)

Hence, the novel compounds are those of the formula I, wherein the abovementioned known compounds are excluded.

Still a further object of the present invention is a process forpreparing the pyrrolidine derivatives according to formula I.

The pyrrolidine derivatives exemplified in this invention can beprepared from readily available starting materials using the followinggeneral methods and procedures. It will be appreciated that wheretypical or preferred experimental conditions (i.e. reactiontemperatures, time, moles of reagents, solvents, etc.) are given, otherexperimental conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvents used, but such conditions can be determined by one skilled inthe art by routine optimisation procedures.

Generally, the pyrrolidine derivatives according to the general formulaI could be obtained by several processes, using both solution-phase andsolid-phase chemistry protocols. Depending on the nature of A, B, and X,certain processes will, in some instances, be preferred over others, andit is assumed that the choice of the most suitable process will be knownto the practitioner skilled in the art.

According to one process, pyrrolidine derivatives according to thegeneral formula I, whereby the substituent B is C(O)—NR⁸R⁹, with R⁸ andR⁹ being defined as above, are prepared from the corresponding suitablyN-protected 4-substituted pyrrolidine derivatives II, whereby thesubstituent X is as above defined, by solution-phase chemistry protocolssuch as described in the Examples and shown in Scheme 1, below. Thesuitably N-protected 4-substituted pyrrolidine derivatives II are firstreacted with primary or secondary amines III, whereby the substituentsR⁸ and R⁹ are as above defined, using conditions and methods well knownto those skilled in the art to prepare an amide from an amine and acarboxylic acid or a carboxylic acid derivative, using standard peptidecoupling agents, such as e.g. DIC, EDC, TBTU, DECP, or others, to yieldcompounds of formula IV. Removal of the N-protecting group using theappropriate deprotection agents produces derivatives of formula V. Thesecan be treated with acylating agents of general formula VI, whereby thesubstituent R¹ is as above defined, while LG could be any appropriateleaving group. Preferred acylating agents VI are acid chlorides (VIa),used in conjunction with a tertiary amine base, or carboxylic acids(VIb), used in conjunction with a peptide coupling agent, e.g. from theabove mentioned group, to yield the products of general formula I, withB being defined as C(O)N⁸R⁹ (Ia).

Other derivatives of formula I are prepared using known modifications tothe Scheme 1 reaction sequence. Compounds of formula I wherein A isdifferent from the carbonyl functionality are prepared by replacingformula VI compounds with compounds containing the appropriatefunctional groups, e.g. sulfonyl chlorides, isocyanates,isothiocyanates, chloroformates, substituted alkyl halides, or others toyield sulfonamide, urea, thiourea, carbamate, substituted alkylderivatives, or others, respectively.

Compounds of formula II, whereby the substituent X is CR⁶R⁷, and R⁶ andR⁷ are as above defined, can be prepared from compounds of generalformula VII by Wittig-type reactions with anions of phosphoranes such asVIIIa and/or of phosphonates such as VIIb, followed by saponification ofthe ester function using standard synthetic techniques, as hereinafterdescribed in the Examples and shown in Scheme 2.

Compounds of general formula VII can be prepared from commerciallyavailable, suitably N-protected 4-hydroxyproline X, by a reactionsequence consisting of oxidation and esterification, using standardsynthetic techniques as hereinafter described in the Examples and shownin Scheme 3.

Compounds of formula II, wherein the substituent X is NOR⁶ or NNR⁶R⁷,and R⁶ and R⁷ are as above defined, can be prepared from compounds ofgeneral formula XI by reaction with substituted hydroxylamines XIIaand/or substituted hydrazines and/or hydrazides XIIb using standardsynthetic techniques as hereinafter described in the Examples and shownin Scheme 4.

Compounds of formula XIIa are commercially available or prepared bystandard synthetic techniques as hereinafter described in the Examples.Compounds of formula II with X═S are accessible from the correspondingsuitably protected ketopyrrolidine intermediates VII through standardfunctional group interconversion methods well known to the personskilled in the art, such as, e.g., by treatment with Lawesson's reagentor others (Pedersen, B. S. et al.; Bull. Soc. Chim. Belg. 1978, 87,223), followed by saponification.

According to another process, pyrrolidine derivatives according to thegeneral formula I, whereby the substituent B is a heterocyclic residueB1 as above defined, and the substituents are as above defined, areprepared from the corresponding suitably N-protected 4-substitutedpyrrolidine derivatives II, whereby the substituent X is as abovedefined, by solution-phase chemistry protocols such as described in theExamples and shown in Scheme 5, below. The starting suitably N-protected4-substituted pyrrolidine derivatives II are first reacted withortho-substituted primary anilines of general formula XIII, whereby thesubstituents Q, Z, E, Y, and R¹¹ are as above defined, using standardpeptide coupling agents, such as DIC, EDC, TBTU, DECP, or others,followed by exposure to dilute weak acid, such as acetic acid, in asuitable organic solvent, such as DCM, to promote cyclisation yieldingcompounds of formula XIV. Removal of the N-protecting group using theappropriate deprotection agents produces cyclic derivatives of formulaXV. These can be treated with acylating agents of general formula VI,whereby the substituent R¹ is as above defined, while LG could be anyappropriate leaving group. Preferred acylating agents VI are acidchlorides (VIa), used in conjunction with a tertiary amine base, orcarboxylic acids (VIb), used in conjunction with a peptide couplingagent, e.g. from the abovementioned group, to yield the products ofgeneral formula I, with B being defined as B1 (Ib).

Other derivatives of formula I are prepared using known modifications tothe Scheme 5 reaction sequence. Compounds of formula I wherein A isdifferent from the carbonyl functionality are prepared by replacingformula VI with compounds containing the appropriate functional groups,e.g. sulfonyl chlorides, isocyanates, isothiocyanates, chloroformates,substituted alkyl halides, or others to yield sulfonamide, urea,thiourea, carbamate, substituted alkyl derivatives, or others,respectively.

According to another general process, summarized in Scheme 6,pyrrolidine derivatives according to the general formula I, whereby thesubstituents A, B, X, and R¹ are as above defined, are prepared fromcompounds of formula XVI, using the synthetic techniques as outlined inSchemes 2 and 4. As further shown in Scheme 6, compounds of formula XVIare accessible either from XI, following, e.g., the syntheticmethodologies introduced in Schemes 1 and 5, or from Ic throughhydrolysis of the methyloxime moiety, e.g. under mild hydrolysisconditions as described hereinafter in the Examples. This presentsynthetic strategy is most preferred when X is NOH or NNR⁶R⁷, wherebythe substituents R⁶ and R⁷ are as above defined.

According to yet another process, pyrrolidine derivatives according tothe general formula I, whereby the substituents A, B, X, and R¹ are asabove defined, are prepared from the corresponding suitably N-protected4-substituted pyrrolidine derivatives II, whereby the substituent X isabove defined, by a solid-phase protocol such as described in theexamples and shown in Scheme 7, below. The N-Boc-protected 4-substitutedpyrrolidine derivative II is reacted e.g. with Kaiser oxime resin usingstandard carbodiimide-mediated coupling conditions well known to thepractitioner skilled in the art, followed by Boc-deprotection withdilute TFA in DCM, or with BF₃.OEt₂ in dilute HOAc in DCM, to givecompound XIX. The latter compound can be treated with acylating agentsof general formula VI, whereby the substituent R¹ is as above defined,while LG could be any appropriate leaving group. Preferred acylatingagents VI are acid chlorides (VIa), used in conjunction with a tertiaryamine base, or carboxylic acids (VIb), used in conjunction with apeptide coupling agent, e.g. DIC or EDC, to yield products of generalformula XX.

Compounds of formula I wherein A is different from the carbonylfunctionality are prepared by replacing formula VI with compoundscontaining the appropriate functional groups, e.g. sulfonyl chlorides,isocyanates, isothiocyanates, chloroformates, substituted alkyl halides,or others to yield sulfonamide, urea, thiourea, carbamate, substitutedalkyl derivatives, or others-respectively.

In order to obtain the final compounds of general formula I, the linkageto the resin is cleaved by prolonged treatment with amines of generalformulae III or XIII and low percentages of a weak acid, such as HOAc.The cycles within the below Scheme 7 illustrate the resign beads towhich the corresponding compounds are linked during the solid phasesynthesis. Other derivatives of formula I are prepared using knownmodifications to, or variations of, the Scheme 7 reaction sequence.Further to the above mentioned Kaiser oxime resin, other suitablereagents, notably resins, known to a person skilled in the art, could beemployed for the solid-phase synthesis of compounds of general formulaI.

The reaction sequences outlined in the above Schemes providesenantiomerically pure compounds of formula I, if enantiomerically purestarting materials are used. (R) as well as (S) enantiomers can beobtained depending upon whether (R) or (S) forms of commerciallyavailable compounds of formulas II, III, VI, and/or X were used as thestarting materials.

However, the reaction sequences outlined in the above Schemes usuallyprovide mixtures of (E) and (Z) isomers with respect to the substituentson the exocyclic double bond of the pyrrolidine ring. In all casesstudied, these (E)/(Z)-isomers could be separated by standardchromatography techniques well known to the person skilled in the art,such as by reversed phase high-pressure liquid chromatography (HPLC) orsilica gel flash chromatography (FC). The assignment of the absoluteconfiguration of the exocyclic double bond was performed usingNMR-techniques well described in the literature as will be known to thepractitioner skilled in the art (for configurationnal assignments ofe.g. oxime functionalities, see e.g. E. Breitmaier, W. Voelter Carbon-13NMR Spectroscopy, 3rd Ed, VCH, 1987, p. 240).

According to a further general process, compounds of formula I can beconverted to alter-native compounds of formula I, employing suitableinterconversion techniques such as hereinafter described in theExamples.

If the above set out general synthetic methods are not applicable forobtaining compounds according to formula I and/or necessaryintermediates for the synthesis of compounds of formula I, suitablemethods of preparation known by a person skilled on the art should beused. In general, the synthesis pathways for any individual compound offormula I will depend on the specific substitutents of each molecule andupon the ready availability of intermediates necessary; again suchfactors being appreciated by those of ordinary skill in the art. For allthe protection, de-protection methods, see Philip J. Kocienski, in“Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and,Theodora W. Greene and Peter G. M. Wuts in “Protective Groups in OrganicSynthesis”, Wiley-Interscience, 1991.

Compounds of this invention can be isolated in association with solventmolecules by crystallization from evaporation of an appropriate solvent.The pharmaceutically acceptable acid addition salts of the compounds offormula I, which contain a basic center, may be prepared in aconventional manner. For example, a solution of the free base may betreated with a suitable acid, either neat or in a suitable solution, andthe resulting salt isolated either by filtration or by evaporation undervacuum of the reaction solvent. Pharmaceutically acceptable baseaddition salts may be obtained in an analogous manner by treating asolution of compound of formula I with a suitable base. Both types ofsalt may be formed or interconverted using ion-exchange resintechniques.

If the above set out general synthetic methods are not applicable forthe obtention of compounds of formula I, suitable methods of preparationknown by a person skilled in the art should be used.

A final aspect of the present invention is related to the use of thecompounds according to formula I for the modulation of the Oxytocinreceptor, the use of said compounds for the preparation ofpharmaceutical compositions for the modulation of the oxytocin receptoras well as the formulations containing the active compounds according toformula I. Said modulation of the oxytocin receptor is viewed as asuitable approach for the treatment of preterm labor, premature birthand dysmenorrhea. Hence, the compounds of the present invention aresuitable for the treatment of preterm labor, premature birth anddysmenorrhea.

When employed as pharmaceuticals, the pyrrolidine derivatives of thepresent invention are typically administered in the form of apharmaceutical composition. Hence, pharmaceutical compositionscomprising a compound of formula I and a pharmaceutically acceptablecarrier, diluent or excipient therefore are also within the scope of thepresent invention. A person skilled in the art is aware of a wholevariety of such carrier, diluent or excipient compounds suitable toformulate a pharmaceutical composition. Also, the present inventionprovides compounds for use as a medicament. In particular, the inventionprovides the compounds of formula I for use as antagonists of theoxytocin receptor, for the treatment or prevention of disorders mediatedby the oxytocin receptor in mammals, notably of humans, either alone orin combination with other medicaments, e.g. in combination with afurther OT antagonist.

The compounds of the invention, together with a conventionally employedadjuvant, carrier, diluent or excipient may be placed into the form ofpharmaceutical compositions and unit dosages thereof, and in such formmay be employed as solids, such as tablets or filled capsules, orliquids such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, or in the form of sterileinjectable solutions for parenteral (including subcutaneous use). Suchpharmaceutical compositions and unit dosage forms thereof may compriseingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

When employed as pharmaceuticals, the pyrrolidine derivatives of thisinvention are typically administered in the form of a pharmaceuticalcomposition. Such compositions can be prepared in a manner well known inthe pharmaceutical art and comprise at least one active compound.Generally, the compounds of this invention are administered in apharmaceutically effective amount. The amount of the compound actuallyadministered will typically be determined by a physician, in the lightof the relevant circumstances, including the condition to be treated,the chosen route of administration, the actual compound administered,the age, weight, and response of the individual patient, the severity ofthe patient's symptoms, and the like.

The pharmaceutical compositions of these inventions can be administeredby a variety of routes including oral, rectal, transdermal,subcutaneous, intravenous, intramuscular, and intranasal. Depending onthe intended route of delivery, the compounds are preferably formulatedas either injectable or oral compositions. The compositions for oraladministration can take the form of bulk liquid solutions orsuspensions, or bulk powders. More commonly, however, the compositionsare presented in unit dosage forms to facilitate accurate dosing. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient. Typical unit dosage forms include prefilled,premeasured ampoules or syringes of the liquid compositions or pills,tablets, capsules or the like in the case of solid compositions. In suchcompositions, the pyrrolidine compound is usually a minor component(from about 0.1 to about 50% by weight or preferably from about 1 toabout 40% by weight) with the remainder being various vehicles orcarriers and processing aids helpful for forming the desired dosingform.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatine; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As above mentioned, the pyrrolidine derivatives of formula Iin such compositions is typically a minor component, frequently rangingbetween 0.05 to 10% by weight with the remainder being the injectablecarrier and the like.

The above described components for orally administered or injectablecompositions are merely representative. Further materials as well asprocessing techniques and the like are set out in Part 8 of Remington'sPharmaceutical Sciences, 17^(th) Edition, 1985, Marck PublishingCompany, Easton, Pa., which is incorporated herein be reference.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can also befound in the incorporated materials in Remington's PharmaceuticalSciences.

In the following the present invention shall be illustrated by means ofsome examples which are not construed to be viewed as limiting the scopeof the invention. The HPLC, NMR and MS data provided in the examplesdescribed below were obtained as followed. The following abbreviationsare hereinafter used in the accompanying examples: min (minute), hr(hour), g (gram), mmol (millimole), m.p. (melting point), eq(equivalents), mL (milliliter), μL (microliters), mL (milliliters), ACN(Acetonitrile), CDCl₃ (deuterated chloroform), cHex (Cyclohexanes), DCM(Dichloromethane), DECP (Diethylcyanophosphonate), DIC (Diisopropylcarbodiimide), DMAP (4-Dimethylaminopyridine) DMF (Dimethylformamide),DMSO (Dimethylsulfoxide), DMSO-d₆ (deuterated dimethylsulfoxide), EDC(1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide), EtOAc (Ethyl acetate),Et₂O (Diethyl ether), HOBt (1-Hydroxybenzotriazole), K₂CO₃ (potassiumcarbonate), NaH (Sodium hydride), NaHCO₃ (Sodium bicarbonate), nBuLi (nButyllithium), TBTU(O-Benzotriazolyl-N,N,N′,N′-tetramethyluronium-tetrafluoroborate), TEA(Triethyl amine), TFA (Trifluoro-acetic acid), THF (Tetrahydrofuran),MgSO₄ (Magnesium sulfate), PetEther (Petroleum ether), rt (roomtemperature).

EXAMPLES Intermediate 1:(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid

Commercial(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid(30 g, 0.13 mol) was dissolved in acetone (1500 ml). A mechanicalstirrer was placed in the flask and the solution stirred vigorously. Afreshly made solution of 8N chromic acid was prepared by dissolvingchromium trioxide (66.7 g, 0.667 mol) in water (40 ml), addingconcentrated sulphuric acid (53.3 ml) and adding enough water to bringthe solution volume to 115 ml. The 8N chromic acid solution (1-15 ml)was then added dropwise over a period of 30 minutes with continuedvigorous stirring, the reaction's exotherm being maintained at theoptimal temperature of 25° C. by the use of an ice bath. After thecomplete addition of the chromic acid, the reaction mixture was stirredfor a further 15 minutes—maintaining the optimal temperature of 25° C.The reaction mixture was then quenched by the addition of methanol (20ml). Exotherm controlled by the use of an ice bath and, if necessary,direct addition of a small amount of crushed ice to the reaction mixtureitself. The reaction mixture was filtered through a Celite pad and thenconcentrated in vacuo. The resulting acidic solution was then extractedwith ethyl acetate (3×300 ml) and the combined organic layers washedwith brine (2×100 ml). Organics then dried with magnesium sulfate andconcentrated in vacuo. Crude product recrystallised from ethyl acetateto give the white crystalline product,(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (22.55g, 76%). The antipodal intermediate,(2R)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid, wasmade according to the same protocol, starting from commercial(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid.

1H NMR (360 MHz, CDCl3); 1.4 (m, 9H), 2.5-3.0 (m, 2H), 3.7-3.9 (m, 2H),4.75 (dd, 1H)

Intermediate 2: 1-tert-butyl 2-methyl(2S)-4-oxo-1,2-pyrrolidinedicarboxylate

A solution of (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylicacid (1 g, 4.3 mmol) in a 1:1 mixture of methanol and toluene (60 ml)was made. Trimethylsilyl diazomethane (6.5 ml of a 2M solution inhexanes, 13 mmol) was then added dropwise to the stirred solution atroom temperature under nitrogen. After completion of the evolution ofnitrogen gas, the resulting yellow solution was evaporated in vacuo, andthe residue filtered through a pad of silica gel, eluting with ethylacetate. Removal of solvent from the filtrate gave a yellow oil (1.05 g,near quantitative yield).

¹H NMR (400 MHz, CDCl₃); 1.4 (m, 9H), 2.5 (m, 1H), 2.8-2.9 (m, 1H) 3.7(s, 3H), 3.9 (m, 2H), 4.6-4.8 (m, 1H).

Intermediate 3: 1-tert-butyl 2-methyl(2S,4EZ)-4-(chloromethylene)-1,2-pyrrolidinedicarboxylate

Chloromethyltriphenylphosphonium iodide (270 mg, 0.62 mmol) was added toa solution of potassium tert-butoxide (67 mg, 0.59 mmol) in anhydrousdiethyl ether (5 ml) under nitrogen and the resulting bright yellowmixture stirred for 30 minutes at ambient temperature. The reaction wasthen cooled to 0° C. and a solution of 1-tert-butyl 2-methyl(2S)-4-oxo-1,2-pyrrolidinedicarboxylate (100 mg, 0.41 mmol in 2 mlanhydrous diethyl ether) was added dropwise. The reaction was thenwarmed to room temperature and stirred for 30 minutes before addingsaturated aqueous ammonium chloride solution (0.5 ml). The organic layerwas removed in vacuo, and the aqueous washed with diethyl ether (3×5ml). The combined organic layers were dried with brine and magnesiumsulfate before filtering and removal of solvent. The desired product wasisolated by silica gel chromatography, eluting with 15% ethyl acetate inhexanes to give 105 mg (93% yield) as a off-white wax.

¹H NMR (400 MHz, CDCl₃); 1.4 (9H, m), 2.6-2.75 (m, 1H), 2.8-3.0 (m, 1H),3.65 (s, 3H), 4.1 (m, 2H), 4.4-4.5 (m, 1H) 5.9-6.0 (m, 1H).

Intermediate 4: 1-tert-butyl 2-methyl(2S)-4-methylene-1,2-pyrrolidinedicarboxylate

Methyltriphenylphosphonium bromide (22 g, 61.6 mmol) was added to asolution of potassium tert-butoxide (6.5 g, 57.6 mmol) in anhydrousdiethyl ether (450 ml) at 0° C. under nitrogen and the resulting brightyellow mixture stirred for 30 minutes. A solution of 1-tert-butyl2-methyl (2S)-4-oxo-1,2-pyrrolidinedicarboxylate (10 g, 41.1 mmol in 150ml anhydrous diethyl ether) was added slowly to the reaction mixture,which was then warmed at 35° C. for 3 h. Saturated aqueous ammoniumchloride solution (0.5 ml) was then added. The organic layer wasremoved, and the aqueous washed with diethyl ether (3×5 ml). Thecombined organic layers were dried with brine and magnesium sulfatebefore filtering and removal of solvent. Silica gel chromatography,eluting with 15% ethyl acetate in hexanes gave the desired product 6.9 g(70% yield) as a off-white wax.

¹H NMR (400 MHz, CDCl₃); 1.4 (9H, m), 2.5 (m, 1H), 2.8 (m, 1H), 3.65 (s,3H), 4.0 (m, 2H), 4.3-4.5 (m, 1H), 4.9 (m, 2H).

Intermediate 5: 1-tert-butyl 2-methyl(2S,4EZ)-4-(cyanomethylene)-1,2-pyrrolidinedicarboxylate

Diethyl cyanomethyl phosphonate (0.86 ml, 4.4 mmol) was dissolved in dryTHF (50 ml) and the solution cooled to 0° C. Sodium hydride (205 mg of a60% suspension in parrafin oil, 5.1 mmol) was then added cautiously andthe reaction stirred for 30 min. The reaction mixture was then cooled to−78° C. and a solution of 1-tert-butyl 2-methyl(2S)-4-oxo-1,2-pyrrolidinedicarboxylate (1.0 g, 4.1 mmol) in dry THF (5ml) was added dropwise. The reaction was then allowed to reach roomtemperature. Saturated aqueous ammonium chloride solution (15 ml) wasthen added, followed by ethyl acetate (100 ml). (The organic layer wasremoved, and the aqueous washed with ethyl acetate (3×5 ml). Thecombined organic layers were dried with brine and magnesium sulfatebefore filtering and removal of solvent. Silica gel chromatography,eluting with 35% ethyl acetate in hexanes gave the desired compound (860mg, 80%) as an off-white wax.

¹H NMR (360 MHz, CDCl₃); 1.4 (m, 9H), 2.7-3.0 (m, 1H), 3.1-3.3 (m, 1H),3.7 (m, 3H), 4.2-4.4 (m, 2H), 4.5-4.7 (m, 1H), 5.4 (m, 1H).

Intermediate 6: 1-tert-butyl 2-methyl(2S,4EZ)-4-benzylidene-1,2-pyrrolidinedicarboxylate

Potassium tert-butoxide (6.1 g, 54 mmol) was added portionwise to asolution of benzyl-triphenylphosphonium chloride (22.45 g, 58 mmol) inanhydrous dichloromethane (400 ml) and the reaction stirred at ambienttemperature for 1 h. The solution was then cooled to 0° C. and asolution of 1-tert-butyl 2-methyl(2S)-4-oxo-1,2-pyrrolidinedicarboxylate (9.36 g, 38.5 mmol) in drydichloromethane (30 ml) was added dropwise. After stirring for a further1 h at 0° C. the reaction was stirred for a further 3 h at ambienttemperature. Saturated aqueous ammonium chloride solution (30 ml) wasthen added. The organic layer was removed, and the aqueous washed withdichloromethane (3×20 ml). The combined organic layers were dried withbrine and magnesium sulfate before filtering and removal of solvent.Silica gel chromatography, eluting with 30% ether in hexanes gave thedesired product 8.65 g (71% yield) as a pale yellow wax.

¹H NMR (400 MHz, CDCl₃);1.5 (m, 9H), 2.8-3.0 (m, 1H), 3.2 (m, 1H), 3.7(m, 3H), 4.2-4.4 (m, 2H), 4.5-4.6 (m, 1H), 6.3-6.4 (m, 1H), 7.1-7.5 (m,5H).

Intermediate 7:(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylicacid

A solution was made containing(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g,21 mmol) and O-methylhydroxylamine hydrochloride (2.7 g, 32.8 mmol) inchloroform (100 ml) containing triethyl-amine (5.5 g, 55 mmol). Thereaction mixture was then stirred at ambient temperature over-night,prior to removal of solvent. The resultant crude reaction mixture wasdissolved in ethyl acetate (150 ml) and washed rapidly with 1N HCl (40ml). The acidic layer was then extracted with ethyl acetate (3×20 ml)and the combined organic layers washed with brine before drying overmagnesium sulfate, filtering and removal of solvent in vacuo. Thedesired product (5.3 g, 94%) was isolated as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃); 1.45 (m, 9H), 2.8-3.2 (m, 2H), 3.9 (s, 3H), 4.2(m, 2H), 4.5-4.7 (m, 1H).

Intermediate 8:(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid

A solution was made containing(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidine-carboxylic acid (5.0 g,22 mmol) and O-ethylhydroxylamine hydrochloride (6.4 g, 65.5 mmol) in a1:1 mixture of pyridine and ethanol (100 ml). The reaction was heated toreflux for 2.5 h before cooling and removal of solvent. The residue wasdissolved in ethyl acetate and washed rapidly with 1.3N HCl (40 ml). Theacidic layer was then extracted with ethyl acetate (3×20 ml) and thecombined organic layers washed with brine before drying over magnesiumsulfate, filtering and removal of solvent in vacuo. The desired product(5.5 g, 93%) was isolated as a pale yellow oil.

¹H NMR (400 MHz, DMSO); 1.3 (t, 3H), 1.55 (m, 9H), 2.9-2.7 (m, 1H),3.4-3.1 (m, 1H), 4.1-4.3 (m, 4H), 4.6 (m, 1H), 12-13.5 (br, 1H).

Intermediate 9:(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidine-carboxylicacid

A solution was made containing(2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidine-carboxylic acid (5.0 g,22 mmol) and O-allylhydroxylamine hydrochloride monohydrate (7.2 g, 65.5mmol) in a 1:1 mixture of pyridine and ethanol (100 ml). The reactionwas heated to reflux for 2.5 h before cooling and removal of solvent.The residue was dissolved in ethyl acetate and washed rapidly with 1.3NHCl (40 ml). The acidic layer was then extracted with ethyl acetate(3×20 ml) and the combined organic layers washed with brine beforedrying over magnesium sulfate, filtering and removal of solvent invacuo. The desired product (5.9 g, 94%) was isolated as a pale yellowoil.

¹H NMR (400 MHz, CDCl₃); 1.5 (m, 9H), 2.8-3.2 (m, 2H), 4.2 (m, 2H),4.5-4.7 (m, 3H), 5.25 (m, 2H), 5.9 (m, 1H), 11.1 (broad S, 1H).

Intermediate 10: 1-[(aminooxy)methyl]-4-methoxybenzene

A solution was made of Boc hydroxylamine (2.0 g, 17.1 mmol) in dry THF(60 ml). Sodium hydride (1.1 g of a 60% suspension in paraffin oil, 25.7mmol) was then added and the suspension stirred. A catalytic amount ofKI was then added to the reaction prior to the cautious addition of4-methoxybenzyl chloride (3.2 g, 20.4 mmol). The reaction was thenallowed to stir overnight before removal of solvent in vacuo. Theresidue was taken up with diethyl ether (100 ml) and HCl gas bubbled infor 20 minutes, causing the start of precipitation of the product. Theflask was stoppered and left to stand overnight. The product was thenfiltered off as a off-white wax (39-52% yield according to varyingbatches).

¹H NMR (400 MHz, D₂O);3.8 (s, 3H), 5 (s, 2H), 7.0 (d, 2H), 7.4 (d, 2H).

Intermediate 11:(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidine-carboxylicacid

The same method as employed in the preparation of Intermediate 7, butstarting from (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylicacid (Intermediate 1) and 1-[(aminooxy)methyl]-4-methoxy-benzene(Intermediate 10) gave the title compound as a gum in a 85% yield.

¹H NMR (400 MHz, DMSO); 1.5 (m, 9H), 2.7-2.9 (m, 1H) 3.9 (s, 3H), 4.2(m, 3H), 4.6 (m, 1H), 5.15 (s, 2H), 7.1 (d, 2H), 7.45 (d, 2H).

Intermediate 12: 2-aminoethyl acetate TFA-salt

A solution was made containing ethanolamine (36.5 ml, 0.6 mol) inchloroform (1000 ml). The Boc₂O (13.1 g, 60 mmol) dissolved inchloroform (600 ml) was slowly added dropwise at 0° C. over a 6-hoursperiod (the temperature was maintained all over this period). Thereaction was allowed to reach room temperature and was stirredovernight. The organic layer was washed with water (2×500 ml), brine anddried over magnesium sulfate before being concentrated in vacuo. Thedesired product (9.5 g, >95%) was isolated as a colourless oil and wasused without further purification. A solution was made containing theBoc-ethanolamine (1.92 g, 12 mmol) with potassium carbonate (5 g, 36mmol) in DCM (40 ml). Acetyl chloride (30 ml, 0.42 mol) was added andthe reaction stirred for 6 hours at room temperature. The excess ofacetyl chloride was removed in vacuo and the crude dissolved in DCM (100ml). The organic layer was washed with water (50 ml), brine and driedover magnesium sulfate before being concentrated in vacuo. The desiredproduct (1.86 g, 77%) was isolated as a colourless oil and was usedwithout further purification. A solution was made containing the O-acyl,Boc-ethanolamine (1.65 g, 8.1 mmol) in DCM (20 ml) and TFA (20 ml) wasadded. After one hour at room temperature, the solvent was removed invacuo. The crude was concentrated from methanol (2-3 times) and from DCM(2-3 times) to give the expected compound (1.75 g, quant.) as an oilused without further purification.

¹H NMR (400 MHz, D₂O); 2.0 (m, 9H), 3.1-3.2 (m, 2H), 4.15-4.25 (m, 2H).

Intermediate 13: 2′-methyl[1,1′-biphenyl]-4-carboxylic acid

To a mixture of 4-bromobenzoic acid (30 g, 0.15 mol),2-methylphenylboronic acid (24 g, 0.15 mol), sodium carbonate (250 g) intoluene (500 mL) and water (500 mL) was added tetrakistriphenylphosphinepalladium(0) (9 g, 0.0074 mol) under nitrogen atmosphere. The reactionmixture was refluxed for 10 h. After this time, 100 ml of 10% NaOH wereadded to the reaction mixture, the aqueous layer was separated andwashed with toluene (2×200 mL). Acidification of the aqueous layer with3N HCl solution gave a solid product, which was filtered, washed withwater and dried. The crude product was then crystallised from toluene toyield 2′-methyl[1,1′-biphenyl]-4-carboxylic acid (20 g, 62.5%).Conversely, the product could also be obtained from1-bromo-2-methylbenzene and 4-carboxybenzeneboronic acid, usinganalogous conditions.

¹H NMR (300 MHz, DMSO); 2.2 (s, 3H), 7.2-7.4 (m, 4H), 7.43 (d, J=9 Hz,2H), 7.99 (d, J=9 Hz, 2H), 13 (b, 1H).

Similarly, using the appropriate commercial boronic acids andarylbromides, the following, related 1,1′-biphenyl intermediates 13 maybe obtained:

4′-methyl[1′,1′-biphenyl]-4-carboxylic acid;2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid;2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid;2-methyl[1,1′-biphenyl]-4-carboxylic acid;3-methyl[1,1′-biphenyl]-4-carboxylic acid;2,2′-dimethyl[1,1′-biphenyl]-4-carboxylic acid;2′-methoxy[1,1′-biphenyl]-4-carboxylic acid;3′-methoxy[1,1′-biphenyl]-4-carboxylic acid;4′-methoxy[1,1′-biphenyl]-4-carboxylic acid;2′-chloro[1,1′-biphenyl]-4-carboxylic acid;3′-chloro[1,1′-biphenyl]-4-carboxylic acid;4′-chloro[1,1′-biphenyl]-4-carboxylic acid;3′,4′-dichloro[1,1′-biphenyl]-4-carboxylic acid;2′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid;3′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid;2′-cyano[1,1′-biphenyl]-4-carboxylic acid;2′,4′-difluoro[1,1′-biphenyl]-4-carboxylic acid; 4-(2-pyridinyl)benzoicacid; 4-(3-pyridinyl)benzoic acid; 4-(4-pyridinyl)benzoic acid;4-(5-pyrimidinyl)benzoic acid.

Intermediate 14: 4-(3-methyl-2-pyridinyl)benzoic acid

A mixture of 2-bromo-3-methylpyridine (22.5 g, 0.1312 mol),4-(hydroxymethyl)phenyl-boronic acid (25 g, 0.164 mol), Pd(PPh₃)₄ (9.5g, 0.0082 mol), and sodium carbonate (200 g in 500 ml of water) intoluene (750 ml) were refluxed under nitrogen atmosphere for 15 h.Separated the toluene layer and distilled under reduced pressure to givea residue. The residue was then purified by column chromatography toyield [4-(3-methyl-2-pyridinyl)-phenyl]methanol (12 g, 47%).

To a solution of [4-(3-methyl-2-pyridinyl)phenyl]methanol (12 g, 0.06mol) in dry DMF (150 mL) was added pyridiniumdichromate (91 g, 0.24 mol)and stirred at RT for 3 days. The reaction mixture was poured into waterand extracted with ethyl acetate (250 mL). The organic layer was washedwith water, brine, dried and concentrated. The crude was purified bycolumn chromatography over silica gel to give4-(3-methyl-2-pyridinyl)benzoic acid (3 g, 25%) as white solid.

¹H NMR (300 MHz, DMSO); 2.3 (s, 3H), 7.33 (dd, J=7.5 Hz, 5 Hz, 1H), 7.67(d, J=8 Hz, 2H), 7.75 (d, J=7.5 Hz, 1H), 8.01 (d, J=8 Hz, 2H), 8.50 (d,J=5 Hz, 1H), 13 (b, 1H).

Intermediate 15: 4-(1-oxido-3-pyridinyl)benzoic acid

To a mixture of 4-tolylboronic acid (38 g, 0.28 mol), 3-bromopyridine(44 g, 0.28 mol), Na₂CO₃ (200 g) in toluene (500 ml) and water (500 ml)was added Pd(PPh₃)₄ (16 g, 0.014 mol), and refluxed for 16 h. Thereaction mixture was cooled, and the separated organic layer was washedwith water and brine, and dried. The solvent was removed to give4-(3-pyridyl)toluene (42 g, 90%).

To a mixture of 4-(3-pyridyl)toluene (35 g, 0.207 mol) in pyridine (400ml) and water (400 ml) was added KMnO₄ (163 g, 1.03 mol) in portions andrefluxed for 12 h. The reaction mixture was filtered through celite andacidified with conc. HCl. The product was washed with water and dried togive 4-(3-pyridyl)benzoic acid (32 g, 76%) as a white solid. To amixture of 4-(3-pyridyl)benzoic acid (22 g, 0.11 mol) in THF (2.51),mCPBA (152 g, 0.44 mol, 50%) was added and stirred at RT for 12 h. Thesolid was filtered, and washed with THF to give4-(1-oxido-3-pyridinyl)benzoic acid (20 g, 86%).

¹H NMR (300 MHz, DMSO); 7.5-7.8 (m, 5H), 7.9 (d, J=8 Hz, 2H), 8.33 (d,J=5 Hz, 2H).

Similarly, starting from 4-tolylboronic acid (45 g, 0.33 mol) and2-bromopyridine (52 g, 0.33 mol), the related intermediate4-(1-oxido-2-pyridinyl)benzoic acid was obtained.

Example 1 General Procedure for the Saponification of the Olefin-TypeProline Methyl Esters, Such as Intermediates 3-6

A solution of sodium hydroxide (4.5 g, 112 mmol) in water (70 ml) wasadded to the relevant proline olefin methyl ester (66 mmol) in 3:1dioxane:water (500 ml) and the reaction stirred for 3 h. The reactionmixture was then washed with diethyl ether (2×50 ml), and the aqueousphase acidified to pH 2 (0.1N HCl) and extracted into ethyl acetate. Theethyl acetate layer was then dried over magnesium sulfate, filtered andthe solvent was then removed in vacuo to give the desired product innear quantitative yields as an oil which was used without furtherpurification.

Example 2 General Protocol for the Solution-Phase Synthesis of OximetherPyrrolidine Derivatives of General Formula Ia (Scheme 1) Method A: e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-methoxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamidea) Protocol for the Formation of the Amide Bond

A solution was made containing the central building block, e.g.(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid (Intermediate 7) (1.5 g, 5.8 mmol), an amine or an amine salt, e.g.2-methoxy-ethylamine (0.51 ml, 5.81 mmol) and DMAP (780 mg, 5.8 mmol) inDCM (30 ml). At 0° C., EDC (1.1 g, 5.8 mmol) was slowly addedportion-wise. The reaction was slowly allowed to reach room temperatureand was stirred overnight. The DCM was evaporated and the crude purifiedby column chromatography using EtOAc (100%) to collect the desiredproduct, e.g. tert-butyl(2S,4EZ)-2-{[(2-meth-oxyethyl)amino]carbonyl}-4-(methoxyimino)-1-pyrrolidinecarboxylate(1.5 g, 80%) as a colourless oil.

¹H NMR (400 MHz, CDCl₃); 1.25 (m, 9H), 2.5-2.9 (m, 2H), 3.1 (s, 3H),3.2-3.3 (m, 4H), 3.65 (s, 3H), 3.8-4.4 (m, 3H), 6.7 (s broad, 1H).

b) Protocol for the N-Deprotection Step

A solution was made containing the amide compounds from the previousstep, e.g. tert-butyl(2S,4EZ)-2-{[(2-methoxyethyl)amino]carbonyl}-4-(methoxyimino)-1-pyrrolidine-carboxylate(1.5 g, 0.4 mmol), in anhydrous ether (35 ml). HCl gas was bubbledslowly through the reaction and the deprotection was followed by TLC.After approximately 20 minutes, the ether was evaporated. The productwas concentrated in vacuo from DCM (2-3 times) to remove the HCl. Thedesired product, e.g.(2S,4EZ)-N-(2-methoxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(1.2 g, quant.) was isolated as a yellow oil and used without furtherpurification.

c) Protocol for the N-Capping Step

A solution was made containing the free NH-compound from the previousstep, e.g. (2S4EZ)-N-(2-methoxyethyl)-4-(ethoxyimino)-2-pyrrolidinecarboxamide (940mg, 3.7 mmol), a carboxylic acid, e.g. [1,1′-biphenyl]-4-carboxylic acid(740 mg, 3.7 mmol) and DMAP (960 mg, 7.8 mmol) in DCM (30 ml). At 0° C.,EDC (715 mg, 3.7 mmol) was slowly added portionwise. The reaction wasslowly allowed to reach room temperature and was stirred overnight. TheDCM was evaporated and the crude purified by column chromatography usingEtOAc (100%) to collect the desired product, e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-methoxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamideas a mixture of two isomers as an off-white solid.

1H NMR (400 MHz, CDCl3); 2.75-2.85 (m, 1H), 3.1-3.3 (m, 4H), 3.4-3.5 (m,4H), 3.8 (m, 3H), 4.1-4.3 (m, 2H), 5.1 (m, 1H), 6.9 (m, 1H), 7.2-7.7 (m,10H). M⁺(APCI⁺); 396.

Method B: e.g. (2S,4E and4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamidea) Protocol for the Formation of the Amide Bond

To a solution of the central building block, e.g.(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid (Intermediate 7) (24.2 mmol, 6.24 g) in dry THF (125 ml) at −25° C.was added NMM (2.5 eq, 60.4 mmol, 6.64 ml) followed byisobutylchloroformate (1.05 eq, 25.4 mmol, 3.3 ml). The resultingmixture was stirred at −25° C. for 30 min and an amine or an amine salt,e.g. (S)-2-amino-1-phenylethanol (1.51 eq, 36.5 mmol, 5 g) was thenadded. The mixture was allowed to gradually warm to rt. After 16 h, thesolvents were removed. The residue was dissolved in AcOEt, washed twicewith NH₄Cl saturated solution, then twice with 10% NaHCO₃ solution. Theorganic layer was dried over Na₂SO₄, filtrated and concentrated toafford the desired product, e.g. tert-butyl(2S,4EZ)-2-({[(2S)-2-hydroxy-2-phenylethyl]amino}carbonyl)-4-(methoxyimino)-1-pyrrolidine-carboxylate(8.76 g, 96%) as a pale yellow oil in 88.5% purity by HPLC.

¹H NMR (CDCl₃: 300 MHz) δ 1.44 (s, 9H, N-Boc), 3.23-2.85 (m, 4H), 3.72(m, 1H), 3.85 (s, 3H, O—CH₃), 4.10 (m, 2H), 4.49 (m, 1H), 4.83 (m, 1H),7.34 (m, 5H, Ar—H); [M+Na⁺] (ESI⁺): 400.

b) Protocol for the N-Deprotection Step

A solution was made containing the amide compounds from the previousstep, e.g. tert-butyl(2S,4EZ)-2-({[(ZS)-2-hydroxy-2-phenylethyl]amino}carbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate(2.64 g, 7 mmol), in anhydrous DCM (35 ml). At 0° C., HCl gas wasbubbled slowly through the reaction and the deprotection was followed byTLC. After approximately 20 minutes, the DCM was evaporated. The productwas concentrated in vacuo from DCM (2-3 times) to remove the HCl. Thedesired product, e.g.(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(1.94 g, quant.) was isolated as a yellow solid and used without furtherpurification.

c) Protocol for the N-Capping Step

To a suspension of 4-(2-methylphenyl)benzoic acid (1.49 g, 7 mmol.) in35 ml DCM, was added oxalyl chloride and DMF (3 ml) under ice cooling.The mixture was stirred for 2 h at rt. The solvent was removed affordingthe corresponding acyl chloride as a yellow solid. It was dissolved inDCM (30 mL) and added slowly on a 0° C. solution containing the freeNH-compound from the previous step, e.g.(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(1.94 g, 7 mmol), and triethylamine (5 eq, 35 mmol, 4.9 ml) in dry DCM(35 ml). The reaction mixture was stirred overnight at r.t.Pol-trisamine was added (2.12 g, 3.45 mmol/g) in order to scavengeexcess of acyl chloride. The mixture was shaken 3 h, filtered and theresulting solution was washed with NH₄Cl sat, brine, and dried overNa₂SO₄. After filtration and evaporation of the solvents, the resultingdark oil (3.26 g) was purified by flash chromatography (Biotage system,column 40M, 90 g SiO₂, with gradients of DCM and MeOH as eluent),affording(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide.Separation of the E/Z-isomers was achieved by several chromatographies,affording(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(230 mg, colorless powder, 98.7% purity by HPLC) and(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(266 mg, colorless powder, 98.3% purity by HPLC).

(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide:M.p. 74° C.; IR (neat) v 3318, 2932, 1613, 1538, 1416, 1239, 1047, 848cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 2.27 (s, 3H, ArCH₃), 2.89 (dd, J=6, 12Hz, 1H),3.18 (br d, J=12 Hz, 1H), 3H), 3.27 (m, 1H), 3.76 (m, 1H), 3.88(s, 3H, NOCH₃), 4.28 (d, J=10 Hz, 1H), 4.47 (d, J=10 Hz, 1H), 4.59 (brs, 1H), 4.88 (m, 1H), 5.20 (m, 1H), 7.03-7.42 (m, 1H, H arom.),7.45-7.54 (m, 2H, H arom.); M⁺(APCI⁺): 472; M⁻(APCI⁻): 470. Analysiscalculated for C₂₈H₂₉N₃O₄ 0.3H₂O: C, 70.51; H, 6.26; N, 8.81. Found: C,70.53; H. 6.30; N, 8.87.

(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide:M.p. 78° C.; IR (neat) v 3318, 2938, 1622, 1538, 1416, 1233, 1045, 852cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 2.28 (s, 3H, ArCH₃), 2.69 (dd, J=6, 10Hz, 1H), 3.02-3.22 (m, 2H), 3.25 (br s, 1H), 3.60 (m, 1H), 3.86 (s, 3H,NOCH₃), 4.14 (m, 2H), 4.71 (m, 1H), 4.96 (m, 1H), 7.03-7.42 (m, 1H, Harom.), 7.45-7.54 (m, 2H, H arom.); M⁺(APCI⁺): 472; M⁻(APCI⁻): 470.Analysis calculated for C₂₈H₂₉N₃O₄ 0.9H₂O: C, 68.95; H, 6.36; N, 8.61.Found: C, 68.87; H, 6.25; N, 8.77.

d) E/Z-Isomerisation

The pure E-isomer was isomerized to a mixture of the E/Z-isomers by thefollowing procedure: the E-isomer was dissolved in dioxane/water 3:1mixture. NaOH (1.7 eq; 0.52 mL of, NaOH 1.6N) was added and theresulting solution was stirred 2 h at r.t. The mixture was neutralisedwith HCl 0.1 N and lyophilised. The components of the resultingE/Z-mixture were separated and purified by flash chromatography usingsame conditions as described above.

Example 3(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[2-(diethylamino)ethyl]-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in, Example 2, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carboxylic acid, andN¹,N¹-diethyl-1,2-ethanediamine the title compound was obtained aftercolumn chromatography as an off-white solid as a mixture of E/Z-isomers.

1H NMR (400 MHz, CDCl3); 1.05-1.15 (m, 6H), 2.7-2.8 (m, 1H), 2.9-3.2 (m,6H), 3.4 (m, 1H), 3.6 (s, 3H), 4.0-4.1 (m, 1H), 4.3-4.4 (m, 1H), 3.75(m, 1H), 3.8 (m, 2H), 6.65 (m, 2H), 7.0-7.1 (m, 2H), 7.2-7.3 (m, 3H),7.35-7.45 (m, 6H), 8.8 (sibr, 0.5H). M⁺(APCI⁺); 543.

Example 4(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 2, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained aftercolumn chromatography as a mixture of E/Z-isomers as an off-white solid.The two isomers could be separated by another flash chromatographicpurification step.

(2S,4E)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide:1H NMR (400 MHz, CDCl3); 2.6-2.7 (m, 1H), 2.8-3.0 (m, 3H), 3.2 (m, 1H),3.4-3.6 (m, 1H), 3.9 (m, 1H), 4.15 (t, 1H), 4.6 (m, 1H), 4.85 (m, 1H),5.75 (s, 1H), 7.0-7.4 (m, 14H). M⁺(APCI⁺); 461.

(2S,4Z)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide:1H NMR (400 MHz, CDCl3); 2.5-2.6 (m, 1H), 2.7-2.9 (m, 1H), 3.0 (m, 1H),3.1-3.4 (m, 1H), 3.4-3.6 (m, 1H), 3.9-4.0 (m, 1H), 4.2-4.4 (m, 2H), 4.6(m, 1H), 4.8-4.9 (m, 1H), 5.75 (s, 1H), 7.0-7.5 (m, 14H). M⁺(APCI⁺);461.

Example 5(2S,4EZ)-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 2, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetic acid, and N¹,N¹-diethyl-1,2-ethanediamine the titlecompound was obtained after column chromatography as an off-white solidas a mixture of E/Z-isomers.

1H NMR (400 MHz, CDCl3); 0.9 (t, 3H), 1.0 (m, 3H), 2.6-3.1 (m, 7H), 3.15(m, 1H), 3.4 (m, 1H), 3.75 (s, 3H), 3.95 (t, 1H), 4.4-4.7 (m, 4H), 5.1(m, 1H), 7.0-7.3 (m, 10H), 9.1 (m, 1H). M⁺(APCI⁺); 451.

Example 6(2S,4EZ)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 2, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, phenoxyacetic acid, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained after column chromatography as an off-white solidas a mixture of E/Z-isomers. The isomers were then separated usingcolumn chromatography.

(2S,4E)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide:1H NMR (360 MHz, CDCl₃); 1.2 (m, 6H), 2.7 (m, 1H), 3.35 (d, 1H), 4.1 (m,4H), 4.3 (d, 1H), 4.45 (d, 1H), 4.7 (m, 2H), 5.15 (d, 1H), 6.9-7.3 (m,10H), 7.9 (d, 1H), 8.15 (m, 1H), 9.0 (br s, 1H). M⁺(APCI⁺); 499.

(2S,4Z)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide:1H NMR (360 MHz, CDCl₃); 1.2 (m, 6H), 2.7 (m, 1H), 3.2 (m, 1H), 4.1 (m,4H), 4.35 (m, 2H), 4.7 (m, 2H), 5.1 (m, 1H), 6.9-7.3 (m, 10H), 7.9 (d,1H), 8.15 (m, 1H), 9.0 (br s, 1H). M⁺(APCI⁺); 499.

Example 7(2S,4EZ)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 2, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carboxylic acid, and9-ethyl-9H-carbazol-3-amine the title compound was obtained after columnchromatography as an off-white solid as a mixture of E/Z-isomers. Theisomers were separated by column chromatography.

(2S,4E)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide:1H NMR (360 MHz, CDCl₃); 0.8 (m, 6H), 1.2 (m. 6H), 2.5 (m, 2H), 3.0 (m,1H), 3.3 (m, 1H), 3.8 (s, 3H), 4.2 (m, 3H), 4.45 (m, 1H), 5.3 (m, 1H),6.1 (d, 1H), 7.1 (m, 1H), 7.2 (m, 1H), 7.3 (d, 1H), 7.35 (m, 1H), 7.55(m, 1H), 7.65 (m, 1H), 8.0 (d, 1H), 8.5 (m, 1H), 9.1 (br S, 1H).M⁺(ES⁺); 543.

(2S,4Z)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide:1H NMR (360 MHz, CDCl₃); 0.8 (m, 6H), 1.2 (m. 6H), 2.5 (m, 2H), 3.05 (m,1H), 3.25 (m, 1H), 3.75 (s, 3H), 4.1 (m, 3H), 4.45 (d, 1H), 5.3 (d, 1H),6.1 (d, 1H), 7.1 (t, 1H), 7.2 (m, 1H), 7.3 (m, 1H), 7.4 (m, 1H), 7.6 (m,1H), 7.7 (m, 1H), 8.0 (d, 1H), 8.45 (m, 1H), 9.1 (m, 1H). M⁺(ES⁺); 543.

Example 8(2S,4EZ)-4-[(allyloxy)imino]-1-benzoyl-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 2, starting from(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, benzoic acid, and 9-ethyl-9H-carbazol-3-amine the title compoundwas obtained after column chromatography as an off-white solid as amixture of E/Z-isomers.

1H NMR (360 MHz, CDCl₃); 1.2 (m, 3H), 2.8 (m, 1H), 3.35 (m, 1H), 4.2 (m,4H), 4.4 (m, 3H), 5.2 (m, 2H), 5.35 (m, 1H), 5.85 (m, 1H), 7.0-7.5 (m,5H), 7.9 (m, 3H), 8.1 (m, 2H), 8.3 (m, 1H), 9.2 (br s, 1H). M⁺(APCI⁺);481.

Example 9 General Protocol for the Solution-Phase Synthesis of OximetherPyrrolidine Derivatives of General Formula I Containing AdditionalReactive Groups;(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamidea) Protocol for the Formation of the Amide Bond

A solution was made containing the central building block, e.g.(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid (Intermediate 7) (575 mg, 2.2 mmol), the amine or amine saltcontaining the suitably protected reactive group, e.g. 2-aminoethylacetate (Intermediate 12) (480 mg, 2.2 mmol) and DMAP (870 mg, 7.1 mmol)in DCM (20 ml). At 0° C., EDC (427 mg, 2.2 mmol) was slowly addedportion-wise. The reaction was slowly allowed to reach room temperatureand was stirred overnight. The DCM was evaporated and the crude purifiedby column chromatography using EtOAc/Hexane: 55/45 to collect thedesired amide compound, e.g. tert-butyl(2S,4EZ)-2-({[2-(acetyloxy)ethyl]-amino}carbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate(373 mg, 49%) as an oil.

1H NMR (400 MHz, CDCl3); 1.7 (m, 9H), 2.1-2.2 (m, 3H), 2.8-3.3 (m, 2H),3.7-3.8 (m, 2H), 4.0-4.1 (m, 3H), 4.2-4.8 (m, 5H), 7.3 (s broad, 1H).

b) Protocol for the N-Deprotection Step

A solution was made containing the Boc-protected compound from theprevious step, e.g. tert-butyl(2S,4EZ)-2-({[2-(acetyloxy)ethyl]amino}carbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate(373 mg, 1.2 mmol) in anhydrous ether (40 ml). HCl gas was bubbledslowly through the reaction and the deprotection was followed by TLC.After approximately 20 minutes, the ether was evaporated. The productwas concentrated in vacuo from DCM (2-3 times) to remove the HCl. Thedesired free NH product, e.g.2-({[(2S,4EZ)-4-(methoxyimino)pyrrolidinyl]carbonyl}amino)ethyl acetate(300 mg, quant.) was isolated as a yellow oil and used without furtherpurification.

1H NMR (400 MHz, D₂O); 1.75 (s, 3H), 2.55-2.65 (m, 1H), 2.8-3.3 (m, 3H),3.45-3.55 (m, 3H), 3.8-4.0 (m, 4H), 4.25-4.35 (m, 1H).

c) Protocol for the N-Capping Step

A solution was made containing the amine-hydrochloride from the previousstep, e.g.2-({[(2S,4EZ)-4-(methoxyimino)pyrrolidinyl]carbonyl}amino)ethyl acetate(560 mg, 2 mmol) and an acid chloride, e.g. [1,1′-biphenyl]-4-carbonylchloride (433 mg, 2 mmol) in DCM (20 ml). Triethylamine (0.7 ml, 5 mmol)was added and the reaction stirred overnight at room temperature. TheDCM was evaporated and the crude purified by column chromatography usingEtOAc (100%) to collect the desired amide compound, e.g.2-({[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]carbonyl}amino)ethylacetate (457 mg, 54%) as an oil.

1H NMR (400 MHz, CDCl3); 1.9 (s, 3H), 2.7-2.8 (m, 1H), 3.2-3.6 (m, 3H),3.75-3.85 (m, 3H), 4.0-4.4 (m, 4H), 5.15-5.25 (m, 1H), 7.2-7.6 (m, 9H).

d) Protocol for the Deprotection of the Reactive Group

A solution was made containing the side-chain protected compound fromthe previous step, e.g.2-({[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]carbonyl}amino)ethylacetate (450 mg, 10.6 mmol) in THF (10 ml). An aqueous solution (10 ml)of sodium hydroxide (75 mg, 19 mmol) with methanol (5 ml) was added andthe reaction stirred at room temperature for three hours. The solventwas removed in vacuo and the crude purified by column chromatographyusing THF (100%) to give the expected final product, e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(300 mg, 75%) as a white solid.

1H NMR (400 MHz, CDCl3); 2.85-3.0 (m, 1H), 3.3-3.6 (m, 3H), 3.7-3.8(2H), 3.85-3.95 (m, 3H), 4.2-4.5 (m, 2H), 5.15-5.25 (m, 1H), 7.2-7.9 (m,9H). M⁺(APCI⁺); 382.

Example 10(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 9, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-amino-1-phenylethylacetate, the title compound was obtained after column chromatography asa mixture of E/Z-isomers as an off-white solid. The two isomers could beseparated by another flash chromatographic purification step.

(2S,4E)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide:1H NMR (400 MHz, CDCl3); 2.75-2.9 (m, 1H), 3.1-3.25 (m, 2H), 3.35-3.6(m, 1H), 3.7-3.8 (m, 1H), 3.75 (s, 3H), 4.1-4.3 (m, 2H), 4.8 (m, 1H),5.1 (dd, 1H), 7.1-7.6 (m, 15H). M⁺(APCI⁺); 458.

(2S,4Z)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide:1H-NMR (400 MHz, CDCl3); 2.7-2.85 (m, 1H), 3.05-3.25 (m, 2H), 3.35 (m,1H), 3.65-3.8 (m, 1H), 3.8 (s, 3H), 4.15-4.25 (d, 1H), 4.25-4.4 (m, 1H),4.75 (m, 1H), 5.1 (dd, 1H), 7.15-7.6 (m, 15H). M⁺(APCI⁺); 458.

Example 11 General Protocol for the Solution-Phase Synthesis ofOximether Pyrrolidine Derivatives of General Formula Ib (Scheme 5);(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-([1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime a) Protocol for the Formation of the Amide Bond

A solution was prepared containing the central building block, e.g.(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid (Intermediate 7) (2.1 g, 8.1 mmol), an ortho-substituted aromaticamine or amine salt, e.g. 1,2-benzenediamine (0.88 g, 8.1 mmol) and DMAP(1.59 g, 13.0 mmol). in dry dichloromethane (30 ml). This solution wascooled to 0° C. and treated with EDC (1.56 g, 8.2 mmol) before warmingto room temperature and stirring for 2 days. The solvent was removed invacuo and the product purified by silica gel chromatography, elutingwith a gradient of 30-80% ethyl acetate in hexane to give the desiredanilide product, e.g. tert-butyl(2S,4EZ)-2-[(2-aminoanilino)carbonyl]-4-(methoxyimino)-1-pyrrolidinecarboxylate2.8 g, 97% as a colourless foam.

1H NMR (360 MHz, CDCl3); 1.7, (m, 9H), 2.5-3.5 (br, 4H), 3.4 (m, 1H),4.0 (m, 3H), 4.2-4.4 (m, 2H), 4.9 (m, 1H), 6.9-7.5 (m, 4H), 8.5 (br,1H).

b) Protocol for the Formation of the Fused Heterocyclic Ring

A solution of the anilide compound from the previous step, e.g.tert-butyl(2S,4EZ)-2-[(2-aminoanilino)carbonyl]-4-(methoxyimino)-1-pyrrolidinecarboxylate(0.8 g, 2.3 mmol) in dichloromethane (30 ml) and acetic acid (3 ml) wasstirred at room temperature for 3 days. Saturated aqueous sodiumbicarbonate (7 ml) was added to the reaction, the organic phasecollected and dried over magnesium sulfate before filtering and removalof solvent in vacuo to give the desired product, e.g. tert-butyl(2S,4EZ)-2-(1H-benzimidazol-2-yl)-4-(methoxy-imino)-1-pyrrolidinecarboxylate(740 mg, 97%) as an off-white foam.

1H NMR (360 MHz, CDCl3); 1.5 (m, 9H), 3.1 (m, 1H), 3.8 (m, 3H) 3.9-4.3(m, 3H), 5.3 (m, 1H), 7.1-7.6 (m, 4H), 10-10.5 (br, 1H).

c) Protocol for the N-Deprotection Step

Hydrogen chloride gas was bubbled into a solution of the fusedheterocyclic product from the previous step, e.g. tert-butyl(2S,4EZ)-2-(1H-benzimidazol-2-yl)-4-(methoxyimino)-1-pyrrolidinecarboxylate(740 mg, 2.2 mmol) in dry DCM (20 ml) for 30 min. The solvent wasremoved in vacuo to give the desired product, e.g.(3EZ,5S)-5-(1H-benzimidazol-2-yl)-3-pyrrolidinone O-methyloxime (0.58 g,99%), as a brown amorphous powder which was used without furtherpurification.

d) Protocol for the N-Capping Step

A solution of the free NH product from the previous step, e.g.(3EZ,5S)-5-(1H-benzimidazol-2-yl)-3-pyrrolidinone O-methyloxime (0.58 g,2.2 mmol) in dry dichloromethane (25 ml) was treated with an acidchloride, e.g. [1,1′-biphenyl]-4-carbonyl chloride (0.48 g, 2.2 mmol)and triethylamine (0.9 ml, 6.6 mmol). The resulting solution was thenstirred for 3 h at room temp before removal of solvent in vacuo and thedesired isomers were isolated by flash chromatography on silica gel,eluting with a gradient of ethyl acetate (10-80%) in hexane to give thetwo isomers (120 mg of the less polar and 400 mg of the more polar) ofthe desired product, e.g. (3E,5S) and(3Z,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime, as off-white powders.

(3E,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime: 1H NMR (360 MHz, CDCl3); 3.2, (m, 1H), 3.8 (s, 3H), 4.0(m, 1H), 4.3 (m, 2H), 6.0 (m, 1H), 6.0 (m, 1H), 7.2-7.7 (m, 13H), 10-11(br, 1H). M⁺(APCI⁺); 411.

(3Z,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime: 1H NMR (360 MHz, CDCl3); 3.1, (m, 1H), 3.8 (s, 3H), 3.9(m, 1H), 4.3 (m, 2H), 6.0 (m, 1H), 6.0 (m, 1H), 7.2-7.7 (m, 13H), 10-11(br, 1H). M⁺(APCI⁺); 411.

Example 12(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)-carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 11, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and1,2-benzenediamine, the title compound was obtained in 91% purity byHPLC. MS(ESI+): m/z=425.

Example 13(3EZ,5S)-5-(1-methyl-1H-benzimidazol-2-yl)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 11, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, andN-methyl-1,2-benzenediamine, the title compound was obtained in 83%purity by HPLC. MS(ESI+): m/z=439.

Example 14(3EZ,5S)-5-(7-hydroxy-1H-benzimidazol-2-yl)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 11, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2,3-diaminophenol,the title compound was obtained in 91% purity by HPLC. MS(ESI+):m/z=441.

Example 15(3EZ,5S)-5-(3,4-dihydro-2-quinazolinyl)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 11, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and2-(aminomethyl)aniline, the title compound was obtained in 77% purity byHPLC. MS(ESI+): m/z=439.

Example 16(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-(1-methyl-1H-benzimidazol-2-yl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 11, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, andN¹-methyl-1,2-benzenediamine, the title compound was obtained in 88%purity by HPLC. MS(ESI+): m/z=425.

Example 17 General Protocol for the Solution-Phase Synthesis of Oxime orHydrazone Pyrrolidine Derivatives of General Formula I (Scheme 6);(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(hydroxyimino)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamidea) Protocol for the Hydrolysis of the Oximether Group.

The starting oximether compounds, e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide,were obtained following the general methods as outlined, e.g., inExample 2, 11 or 22. A solution containing the oximether compound wasprepared, e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(64 mg, 0.14 mmol), paraformaldehyde powder (95%, 42 mg, 1.41 mmol) andAmberlyst® 15 (30 mg) in acetone containing 10% of water (2 mL). Thereaction was stirred 4 h at 60° C. Insoluble materials were filtered offand washed with a small amount of acetone. The filtrate was concentratedand the residue was diluted with DCM (15 mL). The organic solution waswashed with brine (10 mL), dried over Na2SO₄, and concentrated. Thedesired ketocarbonyl product, e.g.(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-oxo-2-pyrrolidinecarboxamide(56 mg, 92%) was isolated as a yellow oil and used without furtherpurification.

b) Protocol for the Formation of Oxime and/or Hydrazone Compounds

A solution was made containing the keto-pyrrolidine derivative from theprevious step, e.g.(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy(2-phenethyl]-4-oxo-2-pyrrolidinecarboxamide(46 mg, 0.11 mmol) and hydroxylamine hydrochloride (12 mg, 0.17 mmol) inchloroform (1 ml) containing triethylamine (29 mg, 0.29 mmol). Thereaction mixture was then stirred at ambient temperature for one day,prior to removal of solvent. The resultant crude reaction mixture waspurified by column chromatography using DCM/MeOH (25:1) to collect thedesired product, e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(hydroxy-imino)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamideas a mixture of two isomers as an off-white solid (46 mg, 96% yield).

¹H NMR (300 MHz, CDCl₃); 2.6-3.3 (m, 4H), 4.0-4.7 (m, 4H), 4.9 (m, 1H),5.5 (m, 1H), 7.1-7.5 (m, 8H), 7.6-7.8 (m, 5H), 8.1 (m, 1H), 10.9 (m,1H). M⁺(APCI⁺); 444.

Example 18(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(dimethylhydrazono)-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 17, starting from(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-oxo-2-pyrrolidinecarboxamideand N,N-dimethylhydrazine, the resultant crude reaction mixture waspurified by column chromatography using DCM/MeOH (30:1) to collect thedesired product, e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(dimethylhydrazono)-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamideas a mixture of two isomers as a light yellow oil in 56% yield (90.2%purity by HPLC).

¹H NMR (300 MHz, CDCl₃); 2.35-2.55 (br s, 3H), 2.40-2.60 (m, 1H),2.75-3.55 (m, 5H), 3.55-3.82 (m, 1H), 3.90-4.4 (m, 2H), 4.83 (m, 1H),4.93-5.35 (m, 1H), 7.18-7.49 (m, 9H), 7.49-7.68 (m, 5H). M⁺(APCI⁺); 471.M⁻(APCI⁻); 469.

Example 19(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methylhydrazono)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 17, starting from(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-oxo-2-pyrrolidinecarboxamideand N-methylhydrazine, the resultant crude reaction mixture was purifiedby column chromatography using DCM/MeOH (30:1) to collect the desiredproduct, e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methylhydrazono)-2-pyrrolidinecarboxamideas a mixture of two isomers as a colorless solid in 57% yield (95.2%purity by HPLC).

¹H NMR (300 MHz, CDCl₃); 2.45-2.70 (m, 1H), 2.85 (br s, 3H, NNHCH₃),2.85-3.5 (m, 2H), 3.51-4.4 (m, 4H), 4.84 (br s, 1H, NNHMe), 4.95-5.35(m, 1H), 7.18-7.67 (m, 14H). M⁺(APCI⁺); 457. M⁻(APCI⁻); 455.

Example 20(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-hydrazono-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 17, starting from(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-oxo-2-pyrrolidinecarboxamideand hydrazine hydrate (4% in EtOH), the resultant crude reaction mixturewas purified by column chromatography using DCM/MeOH (30:1) to collectthe desired product, e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-hydrazono-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamideas a mixture of two isomers as a colorless solid in 63% yield (95.3%purity by HPLC).

¹H NMR (300 MHz, DMSO-d₆, 80° C.); 2.55 (dd, J=9.8; 17.6 Hz, 1H), 2.73(dd, J=9.8; 18.2 Hz, 1H), 3.28 (m, 2H), 4.12 (m, 2H), 4.61 (m, 1H), 4.85(m, 1H), 5.15 (m, 1H), 5.70 (br s, 2H, NH₂N═c), 7.17-7.43 (m, 6H),7.44-7.60 (m, 4H), 7.66-7.77 (m, 5H). M⁺(APCI⁺); 443. M⁻(APCI⁻); 441.

Example 21(2S,4EZ)-4-(acetylhydrazono)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide

A hydrazono pyrrolidine derivative obtained by the general methodoutlined in Example 17, e.g.(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-hydrazono-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide(51 mg, 0.11 mmol) was dissolved in pyridine (1 mL). Acetic anhydride (3eq, 32 μl, 0.35 mmol) was added, and the mixture was stirred overnight.The solvent was evaporated and the resultant crude reaction mixture waspurified by column chromatography using DCM/MeOH (20:1) to collect thedesired product, e.g.(2S,4EZ)-4-(acetylhydrazono)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamideas a mixture of two isomers as a colorless solid in 73% yield (98.4%purity by HPLC).

¹H NMR (300 MHz, DMSO-d₆, 80° C.); 1.99 (br s, 3H, CH₃CON), 2.7-3.4 (m,5H), 4.26 (m, 2H), 4.63 (m, 1H), 4.89 (m, 1H), 5.15 (m, 1H), 7.18-7.44(m, 6H), 7.45-7.62 (m, 4H), 7.66-7.85 (m, 5H), 9.97 (br s, 1H, MeCONHN,major isomer), 10.04 (br s, 1H, MeCONHN, minor isomer). M⁺(ESI⁺); 485.M⁻(ESI⁻); 483.

Example 22 General Protocol for the Solid-Phase Synthesis of PyrrolidineDerivatives of General Formula I a) Loading Step

Kaiser oxime resin (16.5 g, loading 1.57 mmol/g) was added to a solutionof the relevant pyrrolidine carboxylic acid building block (51.8 mmol)and diisopropylcarbodiimide (8.1 ml, 51.8 mmol) in dry dichloromethane(150 ml). The resulting suspension was shaken overnight before filteringat the pump and washing sequentially with DMF, DCM and finally diethylether before drying at room temperature in vacuo.

b) N-Deprotection Step

The resin obtained in the loading step was shaken with a 20% solution oftrifluoroacetic acid in dichloromethane (200 ml) for 30 minutes prior tofiltering at the pump and washing sequentially with aliquots of DMF, DCMand finally diethyl ether before drying at room temperature in vacuo.

c) N-Capping Step

The resin from the previous step was transferred into a 96-wellfilter-plate (approx. 50 mg of dry resin/well) and each well treatedwith an N-reactive derivatising agent, e.g. with either of the followingsolutions:

a) an acid chloride (0.165 mmol) and diisopropylethylamine (0.165 mmol)in dry dichloromethane (1 ml), overnight

b) an acid (0.165 mmol) and DIC (0.165 mmol) in, depending on thesolubility of the carboxylic acid, dry dichloromethane or NMP (1 ml)overnight.

c) an isocyanate (0.165 mmol) in dry THF (1 ml); overnight

d) a sulfonyl chloride (0.165 mmol) and diisopropylethylamine (0.165mmol) in NMP (1 ml), overnight.

e) a benzyl(alkyl)bromide (0.165 mmol) and diisopropylethylamine (0.165mmol) in NMP (1 ml), overnight.

f) a vinyl ketone (0.165 mmol) in THF, overnight

g) diketene (0.165 mmol) in THF, overnight

The plate was then sealed and shaken overnight at ambient temperature.The resins were then filtered, washing the resin sequentially withaliquots of DMF, DCM and finally diethyl ether before drying at roomtemperature in vacuo.

d) Cleavage Step

A solution of amine (0.05 mmol) in 2% AcOH in dichloromethane (1 ml) wasadded to each well containing the resin, from the previous step. Theplate was then sealed and shaken for two days at ambient temperature.The wells were then filtered into a collection plate and the solventremoved in a vacuum centrifuge to yield 2-3 mg of the correspondingproducts, generally obtained as oils. The products were characterised byLC (205 nm) and mass spectrometry (ES+). All of the following exampleswere identified based on the observation of the correct molecular ion inthe mass spectrum, and were shown to be at least 40% pure (usually60-95% pure) by LC.

Example 23(2S,4EZ)-N²-(2-hydroxyethyl)-4-(methoxyimino)-N¹-pentyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 2-aminoethanol the title compound wasobtained in 100% purity by LC/MS. MS(ESI+): m/z=315.2.

Example 24(2S,4EZ)-4-benzylidene-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[2-(diethylamino)-ethyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, andN1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 90%purity by LC/MS. MS(ESI+): m/z=482.4.

Example 25(2S,4EZ)-4-[(allyloxy)imino]-1-(4-cyanobenzoyl)-N-[2-(1H-pyrrol-1-yl)phenyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 2-(1H-pyrrol-1-yl)phenylamine thetitle compound was obtained in 51% purity by LC/MS. MS(ESI+): m/z=454.4.

Example 26(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(2-furylmethyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and2-furylmethylamine the title compound was obtained in 92% purity byLC/MS. MS(ESI⁺): m/z=574.4.

Example 27(2S,4EZ)-4-(methoxyimino)-N¹-(3-methoxyphenyl)-N²-(2-thienylmethyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic-acid,1-isocyanato-3-methoxy-benzene, and 2-thienylmethylamine the titlecompound was obtained in 79% purity by LC/MS. MS(ESI+): m/z=403.2.

Example 28(2S,4EZ)-2-{[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]carbonyl}-4-(methoxyimino)-N-pentyl-1-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 1-(1,3-benzodioxol-5-ylmethyl)piperazinethe title compound was obtained in 72% purity by LC/MS. MS(ESI+):m/z=474.4.

Example 29(2S,4EZ)-4-[(benzyloxy)imino]-1-(4-cyanobenzoyl)-N-(2-furylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 2-furylmethylamine the title compoundwas obtained in 49% purity by LC/MS. MS(ESI+): m/z=443.4.

Example 30(2S,4EZ)-4-[(benzyloxy)imino]-N-[²-(diethylamino)ethyl]-1-(4-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and N1,N1-diethyl-1,2-ethanediamine thetitle compound was obtained in 86% purity by LC/MS. MS(ESI+): m/z=529.6.

Example 314-[((2S,4EZ)-4-[(benzyloxy)imino]-2-{[4-(3,4-dichlorophenyl)-1-piperazinyl]-carbonyl}pyrrolidinyl)carbonyl]benzonitrile

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 1-(3,4-dichlorophenyl)piperazine thetitle compound was obtained in 43% purity by LC/MS. MS(ESI+): m/z=576.6.

Example 32(2S,4EZ)-4-(methoxyimino)-N¹-pentyl-N²-[2-(1H-pyrrol-1-yl)phenyl]-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 2-(1H-pyrrol-1-yl)phenylamine the titlecompound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=412.2.

Example 33(2S,4EZ)-1-acryloyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(2-furylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, acryloyl chloride, and 2-furylmethylamine the title compound wasobtained in 74% purity by LC/MS. MS(ESI+): m/z=436.8.

Example 34(2S,4EZ)-4-(tert-butoxyimino)-N²-cyclopropyl-N¹-(3,5-dichlorophenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, 1,3-dichloro-5-iso-cyanatobenzene, and cyclopropylamine the titlecompound was obtained in 48% purity by LC/MS. MS(ESI+): m/z=427.6.

Example 35(2S,4EZ)-4-[(allyloxy)imino]-N-[2-(diethylamino)ethyl]-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, andN1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 93%purity by LC/MS. MS(ESI+): m/z=475.4.

Example 36(2S,4EZ)-N²-[(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-N¹-(3-methylphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methylbenzene, and (1RS)-2-amino-1-phenylethanolthe title compound was obtained in 100% purity by LC/MS. MS(ESI+):m/z=411.2.

Example 37(2S,4EZ)-1-[(benzoylamino)carbonyl]-N-benzyl-4-[(benzyloxy)imino]-N-methyl-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, benzoyl isocyanate, and N-benzyl-N-methylamine the title compoundwas obtained in 40% purity by LC/MS. MS(ESI+): m/z=485.4.

Example 38(2S,4EZ)-1-(4-cyanobenzoyl)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 72% purity by LC/MS. MS(ESI+): m/z=480.4.

Example 39(2S,4EZ)-4-(methoxyimino)-N¹-(3-methylphenyl)-N²-(2-thienylmethyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methylbenzene, and 2-thienylmethylamine the titlecompound was obtained in 98% purity by LC/MS. MS(ESI+): m/z=387.2.

Example 40(2S,4EZ)-4-(tert-butoxyimino)-N-(2-methoxyethyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and2-methoxyethylamine the title compound was obtained in 75% purity byLC/MS. MS(ESI+): m/z=450.2.

Example 41(3EZ,5S)-5-{[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]carbonyl}-1-benzoyl-3-pyrrolidinoneO-(3,4-dichlorobenzyl)oxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 1-(1,3-benzodioxol-5-ylmethyl)piperazine thetitle compound was obtained in 71% purity by LC/MS. MS(ESI+): m/z=609.8.

Example 42 tert-butyl3-[({(2S,4EZ)-4-(ethoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]pyrrolidinyl}carbonyl)amino]-1-azetidinecarboxylate

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and tert-butyl3-amino-1-azetidinecarboxylate the title compound was obtained in 100%purity by LC/MS. MS(ESI+): m/z=519.6.

Example 43(2S,4EZ)-4-{[(4-methoxybenzyl)oxy]imino}-N-(3-methylphenyl)-2-(4-morpholinylcarbonyl)-1-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methylbenzene, and morpholine the title compoundwas obtained in 41% purity by LC/MS. MS(ESI+): m/z=467.4.

Example 44(2S,4EZ)-N²-cyclopropyl-4-{[(4-methoxybenzyl)oxy]imino}-N¹-pentyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and cyclopropylamine the title compound wasobtained in 75% purity by LC/MS. MS(ESI+): m/z=417.2.

Example 45(3EZ,5S)-5-{[4-(3,4-dichlorophenyl)-1-piperazinyl]carbonyl}-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-3-pyrrolidinoneO-benzyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and1-(3,4-dichlorophenyl)piperazine the title compound was obtained in 47%purity by LC/MS. MS(ESI+): m/z=639.8.

Example 46(2S,4EZ)-4-(tert-butoxyimino)-N-[2-(1H-pyrrol-1-yl)phenyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, and 2-(1H-pyrrol-1-yl)phenylamine the title compound was obtainedin 83% purity by LC/MS. MS(ESI+): m/z=341.2.

Example 471-({(2S,4EZ)-4-(chloromethylene)-1-[(4-chlorophenoxy)acetyl]pyrrolidinyl}-carbonyl)-4-(3,4-dichlorophenyl)piperazine

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, (4-chlorophenoxy)acetyl chloride, and1-(3,4-dichlorophenyl)piperazine the title compound was obtained in 64%purity by LC/MS. MS(ESI+): m/z=543.6.

Example 48(2S,4EZ)-4-[(benzyloxy)imino]-N-(4,6-dimethoxy-2-pyrimidinyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and4,6-dimethoxy-2-pyrimidinamine the title compound was obtained in 62%purity by LC/MS. MS(ESI+): m/z=564.6.

Example 49(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-[4-(dimethylamino)butanoyl]-N-(1-naphthylmethyl-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 4-(dimethylamino)butanoyl chloride, and 1-naphthylmethylamine thetitle compound was obtained in 62% purity by LC/MS. MS(ESI+): m/z=555.6.

Example 50(2S)—N²-(2,1,3-benzothiadiazol-4-yl)-N¹-(3,5-dichlorophenyl)-4-oxo-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxy-carbonyl)-4-oxoproline, 1,3-dichloro-5-isocyanatobenzene,and 2,1,3-benzothiadiazol-4-amine the title compound was obtained in 47%purity by LC/MS. MS(ESI+): m/z=450.6.

Example 51(2S,4EZ)-N-benzyl-4-(chloromethylene)-N-methyl-1-(4-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and N-benzyl-N-methylamine the titlecompound was obtained in 61% purity by LC/MS. MS(ESI+): m/z=461.4.

Example 52(2S,4EZ)-N²-(9-ethyl-9H-carbazol-3-yl)-4-{[(4-methoxybenzyl)oxy]imino}-N¹-(3-methylphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methylbenzene, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 72% purity by LC/MS. MS(ESI+): m/z=590.8.

Example 53(2S)—N-(tert-butyl)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxy-carbonyl)-4-methyleneproline,2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and tert-butylamine thetitle compound was obtained in 100% purity by LC/MS. MS(ESI+):m/z=375.4.

Example 54(2S,4EZ)-4-benzylidene-1-[4-(dimethylamino)butanoyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-(dimethylamino)butanoyl chloride, and 6-quinolinamine the titlecompound was obtained in 71% purity by LC/MS. MS(ESI+): m/z=443.6.

Example 55(2S)-1-[4-(dimethylamino)butanoyl]-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, 4-(dimethylamino)butanoylchloride, and 9-ethyl-9H-carbazol-3-amine the title compound wasobtained in 51% purity by LC/MS. MS(ESI+): m/z=433.6.

Example 56(2S,4EZ)-N-(1,3-benzodioxol-5-ylmethyl)-4-[(benzyloxy)imino]-1-(4-cyanobenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 1,3-benzodioxol-5-ylmethylamine thetitle compound was obtained in 51% purity by LC/MS. MS(ESI+): m/z=497.6.

Example 57(2S)-1-({1-[4-(dimethylamino)butanoyl]-4-methylene-2-pyrrolidinyl}carbonyl)-3-azetidinol

Following the general method as outlined in Example 22, starting from1-(tert-butoxy-carbonyl)-4-methyleneproline, 4-(dimethylamino)butanoylchloride, and 3-azetidinol the title compound was obtained in 100%purity by LC/MS. MS(ESI+): m/z=296.4.

Example 58(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[2-(1H-pyrrol-1-yl)phenyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in 54%purity by LC/MS. MS(ESI+): m/z=623.6.

Example 59(2S,4EZ)-4-benzylidene-1-[(4-chlorophenoxy)acetyl]-N-(3,47-dimethoxy-benzyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, (4-chlorophenoxy)acetyl chloride, and 3,4-dimethoxybenzylamine thetitle compound was obtained in 49% purity by LC/MS. MS(ESI+): m/z=521.6.

Example 60(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(diphenylacetyl)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 2-thienylmethylamine the titlecompound was obtained in 51% purity by LC/MS. MS(ESI+): m/z=592.6.

Example 61(2S,4EZ)-N-(3,4-dimethoxybenzyl)-1-(diphenylacetyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 3,4-dimethoxybenzylamine the titlecompound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=502.6.

Example 62(2S,4EZ)-N¹-(3,5-dichlorophenyl)-4-(ethoxyimino)-N²-[2-(1H-pyrrol-1-yl)phenyl]-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 1,3-dichloro-5-isocyanato-benzene, and2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in 54%purity by LC/MS. MS(ESI+): m/z=500.6.

Example 63(2S,4EZ)-N²-(1,3-benzodioxol-5-ylmethyl)-4-{[(4-methoxybenzyl)-oxy]imino}-N¹-pentyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 1,3-benzodioxol-5-ylmethylamine the titlecompound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=511.4.

Example 64(2S,4EZ)-N-benzyl-4-[(benzyloxy)imino]-1-(diphenylacetyl)-N-methyl-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and N-benzyl-N-methylamine the titlecompound was obtained in 42% purity by LC/MS. MS(ESI+): m/z=532.4.

Example 65(2S,4EZ)-N-(2,13-benzothiadiazol-4-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and2,1,3-benzothiadiazol-4-amine the title compound was obtained in 66%purity by LC/MS. MS(ESI+): m/z=472.4.

Example 66(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 6-quinolinamine the titlecompound was obtained in 79% purity by LC/MS. MS(ESI+): m/z=465.4.

Example 67(2S,4EZ)-1-acetoacetyl-N-benzyl-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2,4-oxetanedione, and benzylamine the title compound was obtainedin 45% purity by LC/MS. MS(ESI+): m/z=332.2.

Example 68(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-furyl-methyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-furylmethylamine thetitle compound was obtained in 70% purity by LC/MS. MS(ESI+): m/z=421.4.

Example 69(2S,4EZ)-1-[(4-chlorophenoxy)acetyl]-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, (4-chlorophenoxy)acetyl chloride, and(1RS)-2-amino-1-phenylethanol the title compound was obtained in 62%purity by LC/MS. MS(ESI+): m/z=590.8.

Example 70(2S,4EZ)-N-allyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and allylamine the titlecompound was obtained in 87% purity by LC/MS. MS(ESI+): m/z=378.2.

Example 71(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(2-thienyl-methyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-thienylmethylamine thetitle compound was obtained in 78% purity by LC/MS. MS(ESI+): m/z=434.4.

Example 72(2S,4EZ)-4-(cyanomethylene)-N-(2-furylmethyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and2-furylmethylamine the title compound was obtained in 34% purity byLC/MS. MS(ESI+): m/z=424.4.

Example 73(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-(methoxy-imino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-furylmethylamine thetitle compound was obtained in 75% purity by LC/MS. MS(ESI+): m/z=418.4.

Example 74(2S,4EZ)-1-acetyl-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, acetyl chloride, and cyclopropylamine the title compound wasobtained in 52% purity by LC/MS. MS(ESI+): m/z=384.4.

Example 75(2S,4EZ)-N-(2-furylmethyl)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and2-furylmethylamine the title compound was obtained in 62% purity byLC/MS. MS(ESI+): m/z=430.4.

Example 76(2S,4EZ)-N-benzyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-methyl-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and N-benzyl-N-methylaminethe title compound was obtained in 67% purity by LC/MS. MS(ESI+):m/z=442.4.

Example 77(2S,4EZ)-1-(diphenylacetyl)-4-(ethoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 2-thienylmethylamine the titlecompound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=462.4.

Example 78(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-4-(cyanomethylene)-1-(diphenylacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 2,1,3-benzothiadiazol-4-amine thetitle compound was obtained in 42% purity by LC/MS. MS(ESI+): m/z=480.4.

Example 79(2S)-1-(diphenylacetyl)-N-(1-naphthylmethyl)-4-oxo-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-oxoproline, diphenylacetyl chloride, and1-naphthylmethylamine the title compound was obtained in 60% purity byLC/MS. MS(ESI+): m/z=463.4.

Example 80(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-(diphenylacetyl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 1,2-benzenediamine the title compoundwas obtained in 72% purity by LC/MS. MS(ESI+): m/z=425.4.

Example 81(2S)-2-[1-([1,1′-biphenyl]-4-ylcarbonyl)-4-methylene-2-pyrrolidinyl]-1H-benzimidazole

Following the general method as outlined in Example 22, starting from1-(tert-butoxy-carbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonylchloride, and 1,2-benzenediamine the title compound was obtained in 73%purity by LC/MS. MS(ESI+): m/z=380.4.

Example 82(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-methoxyethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-methoxyethylamine thetitle compound was obtained in 55% purity by LC/MS. MS(ESI+): m/z=399.6.

Example 83(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-(diphenylacetyl)-3-pyrrolidinoneO-allyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 1,2-benzenediamine the title compoundwas obtained in 63% purity by LC/MS. MS(ESI+): m/z=451.4.

Example 84(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[2-(diethylamino)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, andN1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 90%purity by LC/MS. MS(ESI+): m/z=437.4.

Example 85(2S,4EZ)-1-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, diphenyl-acetyl chloride, and 2-thienylmethylamine the titlecompound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=554.4.

Example 86(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(3,4-dimethoxybenzyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 3,4-dimethoxybenzylaminethe title compound was obtained in 58% purity by LC/MS. MS(ESI+):m/z=488.4.

Example 87(2S,4EZ)-1-acetoacetyl-4-(methoxyimino)-N-(1-naphthylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2,4-oxetanedione, and 1-naphthylmethylamine the title compound wasobtained in 40% purity by LC/MS. MS(ESI+): m/z=382.2.

Example 88(2S,4EZ)-N-allyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(diphenylacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, diphenyl-acetyl chloride, and allylamine the title compound wasobtained in 54% purity by LC/MS. MS(ESI+): m/z=536.6.

Example 89(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N¹-pentyl-N²-(6-quinolinyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 6-quinolinamine the title compound wasobtained in 54% purity by LC/MS. MS(ESI+): m/z=542.6.

Example 90(2S,4EZ)-4-(chloromethylene)-1-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and (1RS)-2-amino-1-phenylethanol thetitle compound was obtained in 87% purity by LC/MS. MS(ESI+): m/z=475.4.

Example 91(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonylchloride, and 2-amino-1-phenyl-ethanol the title compound was obtainedin 74% purity by LC/MS. MS(ESI+): m/z=427.4.

Example 92(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 6-quinolinamine the titlecompound was obtained in 73% purity by LC/MS. MS(ESI+): m/z=468.4.

Example 93(2S,4EZ)-4-benzylidene-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and N1,N1-diethyl-1,2-ethanediamine thetitle compound was obtained in 71% purity by LC/MS. MS(ESI+): m/z=496.4.

Example 94(2S,4EZ)-1-acetoacetyl-4-(methoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2,4-oxetanedione, and 2-thienylmethylamine the title compound wasobtained in 42% purity by LC/MS. MS(ESI+): m/z=338.2.

Example 95(2S,4EZ)-1-acetyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(2-hydroxy-2-phenylethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, acetyl chloride, and (1RS)-2-amino-1-phenylethanol the titlecompound was obtained in 48% purity by LC/MS. MS(ESI+): m/z=464.6.

Example 96(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N¹-(3,5-dichlorophenyl)-N²-(6-quinolinyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1,3-dichloro-5-isocyanatobenzene, and 6-quinolinamine the titlecompound was obtained in 66% purity by LC/MS. MS(ESI+): m/z=617.2.

Example 97(2S,4EZ)-4-(methoxyimino)-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 1-naphthylmethylamine the titlecompound was obtained in 99% purity by LC/MS. MS(ESI+): m/z=432.2.

Example 98(2S,4EZ)-4-(chloromethylene)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and3,4-dimethoxybenzylamine the title compound was obtained in 51% purityby LC/MS. MS(ESI+): m/z=503.4.

Example 99(2S,4EZ)-1-(diphenylacetyl)-4-(methoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 2-thienylmethylamine the titlecompound was obtained in 88% purity by LC/MS. MS(ESI+): m/z=448.4.

Example 100(2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and benzylamine the title compound wasobtained in 82% purity by LC/MS. MS(ESI+): m/z=442.4.

Example 101(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]-imino}-N-[2-(diethylamino)ethyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, andN1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 74%purity by LC/MS. MS(ESI+): m/z=581.6.

Example 102(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-[4-(dimethylamino)butanoyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 4-(dimethylamino)butanoyl chloride, and 6-quinolinamine the titlecompound was obtained in 95% purity by LC/MS. MS(ESI+): m/z=542.6.

Example 103(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and5-ethyl-1,3,4-thiadiazol-2-amine the title compound was obtained in 89%purity by LC/MS. MS(ESI+): m/z=450.2.

Example 104(2S,4EZ)-N-benzyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and benzylamine the titlecompound was obtained in 72% purity by LC/MS. MS(ESI+): m/z=428.2.

Example 105(2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-(ethoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and benzylamine the title compound wasobtained in 53% purity by LC/MS. MS(ESI+): m/z=456.4.

Example 106 (2S4EZ)-N²-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N¹-(3-methoxyphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methoxybenzene, and cyclopropylamine the titlecompound was obtained in 45% purity by LC/MS. MS(ESI+): m/z=491.6.

Example 107(2S,4EZ)-1-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, diphenyl-acetyl chloride, and (1RS)-2-amino-1-phenylethanol thetitle compound was obtained in 66% purity by LC/MS. MS(ESI+): m/z=578.4.

Example 108(2S)—N-(2-furylmethyl)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline,2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 2-furyl-methylamine thetitle compound was obtained in 43% purity by LC/MS. MS(ESI+): m/z=399.2.

Example 109(2S,4EZ)-N-(2,13-benzothiadiazol-4-yl)-1-(diphenylacetyl)-4-(methoxy-imino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 2,1,3-benzothiadiazol-4-amine thetitle compound was obtained in 69% purity by LC/MS. MS(ESI+): m/z=486.4.

Example 110(2S)—N1-(3,5-dichlorophenyl)-N2-(3,4-dimethoxybenzyl)-4-oxo-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxy-carbonyl)-4-oxoproline, 1,3-dichloro-5-isocyanatobenzene,and 3,4-dimethoxybenzylamine the title compound was obtained in 48%purity by LC/MS. MS(ESI+): m/z=466.6.

Example 111(2S,4EZ)-N-benzyl-1-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, diphenyl-acetyl chloride, and benzylamine the title compound wasobtained in 60% purity by LC/MS. MS(ESI+): m/z=548.4.

Example 112(2S,4EZ)-1-benzoyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 6-quinolinamine the title compound wasobtained in 67% purity by LC/MS. MS(ESI+): m/z=533.6.

Example 113(2S,4EZ)-1-acetoacetyl-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 2,4-oxetanedione, and cyclopropylamine the title compound wasobtained in 76% purity by LC/MS. MS(ESI+): m/z=426.6.

Example 114(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N²-[(2RS)-2-hydroxy-2-phenethyl]-N¹-pentyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and (1RS)-2-amino-1-phenylethanol the titlecompound was obtained in 47% purity by LC/MS. MS(ESI+): m/z=535.6.

Example 115(2S,4EZ)-4-[(benzyloxy)imino]-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 1-naphthylmethylamine the titlecompound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=508.4.

Example 116(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-methylene-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxy-carbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonylchloride, and 6-quinolinamine the title compound was obtained in 88%purity by LC/MS. MS(ESI+): m/z=434.2.

Example 117(2S,4EZ)-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(diphenyl-acetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, diphenyl-acetyl chloride, and cyclopropylamine the title compoundwas obtained in 49% purity by LC/MS. MS(ESI+): m/z=536.6.

Example 118(2S,4EZ)-1-(4-cyanobenzoyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 6-quinolinamine the title compoundwas obtained in 52% purity by LC/MS. MS(ESI+): m/z=558.6.

Example 119(2S)-4-oxo-1-(phenoxyacetyl)-N-[2-(1H-pyrrol-1-yl)phenyl]-2-1)pyrrolidinecarboxamide

Following, the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-oxoproline, phenoxyacetyl chloride, and2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in 42%purity by LC/MS. MS(ESI+): m/z=404.2.

Example 120(2S,4EZ)-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(methoxy-acetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and cyclopropylamine the title compoundwas obtained in 54% purity by LC/MS. MS(ESI+): m/z=414.6.

Example 121(2S,4EZ)-N-(1,3-benzodioxol-5-ylmethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and1,3-benzodioxol-5-ylmethylamine the title compound was obtained in 64%purity by LC/MS. MS(ESI+): m/z=472.4.

Example 122(3EZ,5S)-5-[(4-acetyl-1-piperazinyl)carbonyl]-1-acryloyl-3-pyrrolidinoneO-(3,4-dichlorobenzyl)oxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, acryloyl chloride, and 1-acetylpiperazine the title compound wasobtained in 79% purity by LC/MS. MS(ESI+): m/z=467.6.

Example 123(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonylchloride, and 2-furylmethylamine the title compound was obtained in 94%purity by, LC/MS. MS(ESI+): m/z=387.2.

Example 124(2S,4EZ)-4-(cyanomethylene)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and3,4-dimethoxybenzylamine the title compound was obtained in 65% purityby LC/MS. MS(ESI+): m/z=494.4.

Example 125(2S,4EZ)-1-[(benzoylamino)carbonyl]-4-(cyanomethylene)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, benzoyl isocyanate, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=492.4.

Example 126(2S,4EZ)-1-benzoyl-N-[2-(diethylamino)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and N1,N1-diethyl-1,2-ethanediamine the titlecompound was obtained in 80% purity by LC/MS. MS(ESI+): m/z=361.2.

Example 127(2S,4EZ)-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl)-4-(ethoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and N1,N1-diethyl-1,2-ethanediamine thetitle compound was obtained in 50% purity by LC/MS. MS(ESI+): m/z=465.4.

Example 128(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-4-[(benzyloxy)imino]-1-(4-cyanobenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 2,1,3-benzothiadiazol-4-amine thetitle compound was obtained in 55% purity by LC/MS. MS(ESI+): m/z=497.4.

Example 129(2EZ)-[5-(1H-benzimidazol-2-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinylidene]ethanenitrile

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 1,2-benzenediamine thetitle compound was obtained in 70% purity by LC/MS. MS(ESI+): m/z=405.2.

Example 130(2S,4EZ)-4-(chloromethylene)-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=488.6.

Example 131(2S)—N²-(9-ethyl-9H-carbazol-3-yl)-N¹-(3-methoxyphenyl)-4-methylene-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline,1-isocyanato-3-methoxybenzene, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 47% purity by LC/MS. MS(ESI+): m/z=469.4.

Example 132(2S,4EZ)-4-(cyanomethylene)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in36% purity by LC/MS. MS(ESI+): m/z=345.2.

Example 133(2S,4EZ)-1-(4-cyanobenzoyl)-N-[2-(diethylamino)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and N1,N1-diethyl-1,2-ethanediamine thetitle compound was obtained in 58% purity by LC/MS. MS(ESI+): m/z=386.2.

Example 1344-{[(2S,4EZ)-2-(1H-benzimidazol-2-yl)-4-(cyanomethylene)pyrrolidinyl]-carbonyl}benzonitrile

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 1,2-benzenediamine the title compoundwas obtained in 84% purity by LC/MS. MS(ESI+): m/z=354.2.

Example 135(2S,4EZ)-4-[(allyloxy)imino]-1-[4-(dimethylamino)butanoyl]-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-(dimethylamino)-butanoyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 40%purity by LC/MS. MS(ESI+): m/z=490.4.

Example 136(2S,4EZ)-4-benzylidene-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in53% purity by LC/MS. MS(ESI+): m/z=396.2.

Example 137(2S,4EZ)-4-benzylidene-1-[4-(dimethylamino)butanoyl]-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-(dimethylamino)butanoyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 74%purity by LC/MS. MS(ESI+): m/z=509.4.

Example 138(2S,4EZ)-4-(chloromethylene)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in73% purity by LC/MS. MS(ESI+): m/z=354.4.

Example 139(2S)—N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 71%purity by LC/MS. MS(ESI+): m/z=320.2.

Example 140(2S,4EZ)-4-(cyanomethylene)-N-(9-ethyl-9H-carbazol-3-yl)-1-(4-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 37% purity by LC/MS. MS(ESI+): m/z=541.4.

Example 141N-{[(2S,4EZ)-2-(1H-benzimidazol-2-yl)-4-(chloromethylene)pyrrolidinyl]-carbonyl}benzamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, benzoyl isocyanate, and 1,2-benzenediamine the title compound wasobtained in 51% purity by LC/MS. MS(ESI+): m/z=381.4.

Example 142(2S)—N¹-(3,5-dichlorophenyl)-N²-(9-ethyl-9H-carbazol-3-yl)-4-methylene-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline,1,3-dichloro-5-isocyanatobenzene, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 40% purity by LC/MS. MS(ESI+): m/z=507.6.

Example 143(2S)-1-(diphenylacetyl)-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, diphenylacetyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 42%purity by LC/MS. MS(ESI+): m/z=514.4.

Example 144(2S,4EZ)-1-benzoyl-4-(chloromethylene)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 48% purity by LC/MS. MS(ESI+): m/z=458.4.

Example 145(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(cyanomethylene)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 32%purity by LC/MS. MS(ESI+): m/z=525.4.

Example 146(2S,4EZ)-4-(cyanomethylene)-N-(9-ethyl-9H-carbazol-3-yl)-1-(3-oxobutyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, 3-buten-2-one, and 9-ethyl-9H-carbazol-3-amine the title compoundwas obtained in 59% purity by LC/MS. MS(ESI+): m/z=415.2.

Example 147(2S)-1-[(4-chlorophenoxy)acetyl]-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, (4-chlorophenoxy)acetylchloride, and 9-ethyl-9H-carbazol-3-amine the title compound wasobtained in 100% purity by LC/MS. MS(ESI+): m/z=488.4.

Example 148(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonylchloride, and 9-ethyl-9H-carbazol-3-amine the title compound wasobtained in 46% purity by LC/MS. MS(ESI+): m/z=500.4.

Example 1492-[(2S,4EZ)-4-(chloromethylene)pyrrolidinyl]-1H-benzimidazole

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, and 1,2-benzenediamine the title compound was obtained in 43%purity by LC/MS. MS(ESI+): m/z=234.4.

Example 150(2S,4EZ)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in91% purity by LC/MS. MS(ESI+): m/z=365.2.

Example 151(2S)-1-benzoyl-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, benzoyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 52%purity by LC/MS. MS(ESI+): m/z=424.2.

Example 152(2S,4EZ)-N-[2-(diethylamino)ethyl]-1-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and N1,N1-diethyl-1,2-ethanediamine thetitle compound was obtained in 56% purity by LC/MS. MS(ESI+): m/z=557.4.

Example 144153(2S,4EZ)-1-benzoyl-N-(2-furylmethyl)-4-{[(4-methoxybenzyl)oxy]-imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 2-furylmethylamine the title compound wasobtained in 40% purity by LC/MS. MS(ESI+): m/z=448.2.

Example 154(2S,4EZ)-4-(tert-butoxyimino)-N-[2-(diethylamino)ethyl]-1-(diphenyl-acetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and N1,N1-diethyl-1,2-ethanediamine thetitle compound was obtained in 80% purity by LC/MS. MS(ESI+): m/z=493.4.

Example 155(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(3,4-dimethoxybenzyl)-4-methylene-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonylchloride, and 3,4-dimethoxybenzyl-amine the title compound was obtainedin 72% purity by LC/MS. MS(ESI+): m/z=457.2.

Example 156(2S,4EZ)-4-(cyanomethylene)-N¹-(3,5-dichlorophenyl)-N²-(9-ethyl-9H-carbazol-3-yl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, 1,3-dichloro-5-isocyanatobenzene, and 9-ethyl-9H-carbazol-3-aminethe title compound was obtained in 60% purity by LC/MS. MS(ESI+):m/z=532.8.

Example 157(2S,4EZ)-4-[(allyloxy)imino]-N²-(9-ethyl-9H-carbazol-3-yl)-N¹-phenyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, isocyanato-benzene, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 67% purity by LC/MS. MS(ESI+): m/z=496.4.

Example 158(2S)—N²-(9-ethyl-9H-carbazol-3-yl)-4-methylene-N¹-phenyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, isocyanatobenzene, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 66%purity by LC/MS. MS(ESI+): m/z=439.2.

Example 159(2S,4EZ)-N²-(2,1,3-benzothiadiazol-4-yl)-N¹-(3,5-dichlorophenyl)-4-(methoxyimino)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1,3-dichloro-5-isocyanatobenzene, and2,1,3-benzothiadiazol-4-amine the title compound was obtained in 55%purity by LC/MS. MS(ESI+): m/z=479.6.

Example 160(2EZ)-[5-(1H-benzimidazol-2-yl)-1-(4-phenoxybenzoyl)-3-pyrrolidinylidene]ethanenitrile

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and 1,2-benzenediamine the titlecompound was obtained in 90% purity by LC/MS. MS(ESI+): m/z=421.2.

Example 161(2S,4EZ)-4-(tert-butoxyimino)-1-(2-ethoxy-1-naphthoyl)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, 2-ethoxy-1-naphthoyl chloride, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 47% purity by LC/MS. MS(ESI+): m/z=591.4.

Example 162(2S,4EZ)-1-benzoyl-N-[2-(diethylamino)ethyl]-4-(ethoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and N1,N1-diethyl-1,2-ethanediamine the titlecompound was obtained in 84% purity by LC/MS. MS(ESI+): m/z=375.2.

Example 163(2S,4EZ)-N²-(2,1,3-benzothiadiazol-4-yl)-4-[(benzyloxy)imino]-N¹-phenyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, isocyanatobenzene, and 2,1,3-benzothiadiazol-4-amine the titlecompound was obtained in 57% purity by LC/MS. MS(ESI+): m/z=487.4.

Example 164(2S,4EZ)-1-(4-cyanobenzoyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(1-naphthylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 1-naphthylmethylamine the titlecompound was obtained in 39% purity by LC/MS. MS(ESI+): m/z=571.6.

Example 165(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-benzoyl-4-{[(4-methoxybenzyl)-oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 2,1,3-benzothiadiazol-4-amine the titlecompound was obtained in 61% purity by LC/MS. MS(ESI+): m/z=502.4.

Example 166(2S,4EZ)-4-[(allyloxy)imino]-N-(2,1,3-benzothiadiazol-4-yl)-1-(diphenylacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 2,1,3-benzothiadiazol-4-amine thetitle compound was obtained in 46% purity by LC/MS. MS(ESI+): m/z=512.4.

Example 167(2S,4EZ)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 75%purity by LC/MS. MS(ESI+): m/z=557.4.

Example 168(2S,4EZ)-1-benzoyl-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=469.4.

Example 169(2S,4EZ)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-(methoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,5,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 88% purity by LC/MS. MS(ESI+): m/z=437.2.

Example 170(2S,4EZ)-4-[(benzyloxy)imino]-N²-(9-ethyl-9H-carbazol-3-yl)-N¹-pentyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 1-isocyanato-pentane, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=540.4.

Example 171(3EZ,5S)-1-benzoyl-5-{[4-(3,4-dichlorophenyl)-1-piperazinyl]carbonyl}-3-pyrrolidinoneO-ethyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 1-(3,4-dichlorophenyl)piperazine the titlecompound was obtained in 51% purity by LC/MS. MS(ESI+): m/z=489.6.

Example 172(2S,4EZ)-4-[(allyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 48%purity by LC/MS. MS(ESI+): m/z=569.4.

Example 173(2S,4EZ)-4-{[(4-methoxybenzyl)oxy]imino}-N-(2-methoxyethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, and 2-methoxyethylamine the title compound was obtained in 52%purity by LC/MS. MS(ESI+): m/z=322.2.

Example 174(2S,4EZ)-4-[(allyloxy)imino]-N-(3,4-dimethoxybenzyl)-1-(diphenylacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 3,4-dimethoxybenzylamine the titlecompound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=528.4.

Example 175(2S,4EZ)-4-[(allyloxy)imino]-1-(4-cyanobenzoyl)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 43%.purity by LC/MS. MS(ESI+): m/z=506.4.

Example 176(2S,4EZ)-4-{[(4-methoxybenzyl)oxy]imino}-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinaminethe title compound was obtained in 61% purity by LC/MS. MS(ESI+):m/z=583.4.

Example 177(2S,4EZ)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in46% purity by LC/MS. MS(ESI+): m/z=351.2.

Example 178(2S,4EZ)-N²-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-N¹-(3-methoxyphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methoxybenzene, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 100% purity by LC/MS. MS(ESI+):m/z=500.4.

Example 179(2S,4EZ)-4-(ethoxyimino)-N²-(9-ethyl-9H-carbazol-3-yl)-N-(3-methoxy-phenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methoxy-benzene, and 9-ethyl-9H-carbazol-3-aminethe title compound was obtained in 60% purity by LC/MS. MS(ESI+): m/z514.4.

Example 180(2S,4EZ)-1-[(4-chlorophenoxy)acetyl]-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, (4-chlorophenoxy)acetyl chloride, and 9-ethyl-9H-carbazol-3-aminethe title compound was obtained in 100% purity by LC/MS. MS(ESI+):m/z=533.4.

Example 181(2S,4EZ)-4-[(allyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-(4-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=573.4.

Example 182(2S,4EZ)-N¹-benzoyl-N²-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, benzoyl isocyanate, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 59% purity by LC/MS. MS(ESI+): m/z=498.4.

Example 183(2S,4EZ)-4-[(benzyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 93%purity by LC/MS. MS(ESI+): m/z=619.6.

Example 184(2S,4EZ)-1-acetyl-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, acetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 87% purity by LC/MS. MS(ESI+): m/z=407.2.

Example 185(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 70%purity by LC/MS. MS(ESI+): m/z=545.4.

Example 186(2S,4EZ)-1-acetyl-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, acetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 69% purity by LC/MS. MS(ESI+): m/z=393.2.

Example 187(2S,4EZ)-1-(diphenylacetyl)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxy-imino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 77% purity by LC/MS. MS(ESI+): m/z=545.4.

Example 188(2S,4EZ)-4-[(allyloxy)imino]-N¹-benzoyl-N²-(9-ethyl-9H-carbazol-3-yl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, benzoyl isocyanate, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=524.4.

Example 189(2S,4EZ)-N²-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-N¹-(3-methyl-phenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methylbenzene, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 89% purity by LC/MS. MS(ESI+): m/z=484.4.

Example 190(2S,4EZ)-4-{[(4-methoxybenzyl)oxy]imino}-N¹-pentyl-N²-(2-thienyl-methyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 2-thienylmethylamine the title compoundwas obtained in 86% purity by LC/MS. MS(ESI+): m/z=473.2.

Example 191(2S,4EZ)-4-(ethoxyimino)-1-(methoxyacetyl)-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and 6-quinolinamine the title compound wasobtained in 81% purity by LC/MS. MS(ESI+): m/z=371.2.

Example 192(2S,4EZ)-4-[(allyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in80% purity by LC/MS. MS(ESI+): m/z=377.2.

Example 193(2S,4EZ)-4-[(benzyloxy)imino]-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinaminethe title compound, was obtained in 48% purity by LC/MS. MS(ESI+):m/z=553.4.

Example 194(2S,4EZ)-4-[(allyloxy)imino]-N-[2-(diethylamino)ethyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, and N1,N1-diethyl-1,2-ethanediamine the title compound wasobtained in 78% purity by LC/MS. MS(ESI+): m/z=283.0.

Example 195(2S,4EZ)-1-[4-(dimethylamino)butanoyl]-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(dimethylamino)-butanoyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 42%purity by LC/MS. MS(ESI+): m/z=464.2.

Example 196(2S)-2-[(3-hydroxy-1-azetidinyl)carbonyl]-N-(3-methoxyphenyl)-4-oxo-1-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-oxoproline, 1-isocyanato-3-methoxybenzene, and3-azetidinol the title compound was obtained in 87% purity by LC/MS.MS(ESI+): m/z=334.2.

Example 197(2S,4EZ)-4-[(benzyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 65% purity by LC/MS. MS(ESI+): m/z=561.4.

Example 198(2S)—N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline,2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 70%purity by LC/MS. MS(ESI+): m/z=512.4.

Example 199(2S,4EZ)-N-(9-ethyl-9H-carbazol-3-yl)-1-(methoxyacetyl)-4-(methoxy-imino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 73% purity by LC/MS. MS(ESI+): m/z=423.4.

Example 200(2S,4EZ)-N²-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-N¹-pentyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 81% purity by LC/MS. MS(ESI+): m/z=464.2.

Example 201(2S,4EZ)-4-(ethoxyimino)-N¹-pentyl-N²-[2-(1H-pyrrol-1-yl)phenyl]-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and 2-(1H-pyrrol-1-yl)phenylamine the titlecompound was obtained in 83% purity by LC/MS. MS(ESI+): m/z=426.2.

Example 202(2S,4EZ)-4-[(allyloxy)imino]-N-(2-methoxyethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, and 2-methoxyethyl-amine the title compound was obtained in 100%purity by LC/MS. MS(ESI+): m/z=242.0.

Example 203(2S,4EZ)-4-(tert-butoxyimino)-N²-(2-methoxyethyl)-N¹-(3-methoxyphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methoxybenzene, and 2-methoxyethylamine the titlecompound was obtained in 76% purity by LC/MS. MS(ESI+): m/z=407.2.

Example 204(2S,4EZ)-4-[(allyloxy)imino]-N²-(2-methoxyethyl)-N¹-(3-methylphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methyl-benzene, and 2-methoxyethylamine the titlecompound was obtained in 85% purity by LC/MS. MS(ESI+): m/z=375.2.

Example 205(2S,4EZ)-1-benzoyl-4-benzylidene-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 81% purity by LC/MS. MS(ESI+): m/z=500.4.

Example 206(2S,4EZ)-N²-benzyl-4-benzylidene-N²-methyl-N¹-(3-methylphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methylbenzene, and N-benzyl-N-methylamine the titlecompound was obtained in 68% purity by LC/MS. MS(ESI+): m/z=440.2.

Example 207(2S,4EZ)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-1-(4-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 99% purity by LC/MS. MS(ESI+): m/z=561.4.

Example 208(2S,4EZ)-4-(ethoxyimino)-N²-(9-ethyl-9H-carbazol-3-yl)-N¹-(3-methyl-phenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methylbenzene, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 80% purity by LC/MS. MS(ESI+): m/z=498.4.

Example 209(2S,4EZ)-4-(methoxyimino)-1-(phenoxyacetyl)-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 6-quinolinamine the title compound wasobtained in 100% purity by LC/MS. MS(ESI+): m/z=419.2.

Example 210(2S,4EZ)-4-(tert-butoxyimino)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and3,4-dimethoxybenzylamine the title compound was obtained in 63% purityby LC/MS. MS(ESI+): m/z=542.4.

Example 211(2S,4EZ)-4-(tert-butoxyimino)-N-cyclopropyl-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and cyclopropylamine the title compoundwas obtained in 73% purity by LC/MS. MS(ESI+): m/z=374.2.

Example 212(2S,4EZ)-4-[(benzyloxy)imino]-N-(tert-butyl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and tert-butylamine the title compound wasobtained in 100% purity by LC/MS. MS(ESI+): m/z=424.2.

Example 213(2S,4EZ)-N-(4,6-dimethoxy-2-pyrimidinyl)-4-(ethoxyimino)-1-(4-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and 4,6-dimethoxy-2-pyrimidinamine thetitle compound was obtained in 79% purity by LC/MS. MS(ESI+): m/z=506.4.

Example 214(4ZE)-4-[(allyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=511.4.

Example 215(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 66%purity by LC/MS. MS(ESI+): m/z=531.4.

Example 216(3EZ,5S)-1-[4-(dimethylamino)butanoyl]-5-(1-piperidinylcarbonyl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(dimethylamino)butanoyl chloride, and piperidine the titlecompound was obtained in 100% purity by LC/MS. MS(ESI+): m/z=339.2.

Example 217(2S,4EZ)-1-acetoacetyl-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2,4-oxetanedione, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 42% purity by LC/MS. MS(ESI+): m/z=435.2.

Example 218(2S,4EZ)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinaminethe title compound was obtained in 57% purity by LC/MS. MS(ESI+):m/z=477.2.

Example 219(2S,4EZ)-N-(9-ethyl-9H-carbazol-3-yl)-4-{[(4-methoxybenzyl)oxy]imino}-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 57%purity by LC/MS. MS(ESI+): m/z=649.4.

Example 220(2S,4EZ)-N²-allyl-N¹-benzoyl-4-(methoxyimino)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, benzoyl isocyanate, and allylamine the title compound was obtainedin 49% purity by LC/MS. MS(ESI+): m/z=345.0.

Example 221(2S,4EZ)-4-[(benzyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-(methoxy-acetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 46% purity by LC/MS. MS(ESI+): m/z=499.2.

Example 222(2S,4EZ)-N¹-(3,5-dichlorophenyl)-N²-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1,3-dichloro-5-isocyanatobenzene, and 9-ethyl-9H-carbazol-3-aminethe title compound was obtained in 42% purity by LC/MS. MS(ESI+):m/z=538.2.

Example 223(2S,4EZ)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-1-(4-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 43% purity by LC/MS. MS(ESI+): m/z=547.2.

Example 224(2S,4EZ)-N-(3,5-dichlorophenyl)-4-(ethoxyimino)-N²-(9-ethyl-9H-carbazol-3-yl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 1,3-dichloro-5-isocyanato-benzene, and 9-ethyl-9H-carbazol-3-aminethe title compound was obtained in 43% purity by LC/MS. MS(ESI+):m/z=552.6.

Example 225(3EZ,5S)-5-{[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]carbonyl}-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-3-pyrrolidinoneO-(tert-butyl)oxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and1-(1,3-benzodioxol-5-ylmethyl)piperazine the title compound was obtainedin 59% purity by LC/MS. MS(ESI+): m/z=595.4.

Example 226(2S,4EZ)-4-benzylidene-N-(9-ethyl-9H-carbazol-3-yl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 47%purity by LC/MS. MS(ESI+): m/z=588.4.

Example 227(2S,4EZ)-4-[(allyloxy)imino]-1-benzoyl-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 6-quinolinamine the title compound wasobtained in 83% purity by LC/MS. MS(ESI+): m/z=415.2.

Example 228(2S,4EZ)-4-[(allyloxy)imino]-1-(methoxyacetyl)-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and 6-quinolinamine the title compound wasobtained in 71% purity by LC/MS. MS(ESI+): m/z=383.0.

Example 229(2S,4EZ)-4-[(allyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-1-(methoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=449.2.

Example 230(2S,4EZ)-4-[(allyloxy)imino]-1-(2-ethoxy-1-naphthoyl)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-ethoxy-1-naphthoyl chloride, and 9-ethyl-9H-carbazol-3-amine thetitle compound was obtained in 60% purity by LC/MS. MS(ESI+): m/z=575.4.

Example 231(2S,4EZ)-4-[(allyloxy)imino]-1-[(4-chlorophenoxy)acetyl]-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, (4-chlorophenoxy)acetyl chloride, and 9-ethyl-9H-carbazol-3-aminethe title compound was obtained in 78% purity by LC/MS. MS(ESI+):m/z=545.4.

Example 232(2S,4EZ)-4-[(allyloxy)imino]-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and9-ethyl-9H-carbazol-3-amine the title compound was obtained in 51%purity by LC/MS. MS(ESI+): m/z=557.2.

Example 233(2S,4EZ)-4-[(allyloxy)imino]-1-(diphenylacetyl)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, diphenylacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the titlecompound was obtained in 43% purity by LC/MS. MS(ESI+): m/z=571.2.

Example 234(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(tert-butyl)-4-(chloromethylene)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and tert-butylamine the titlecompound was obtained in 80% purity by LC/MS. MS(ESI+): m/z=397.6.

Example 235 tert-butyl3-[({4-methylene-1-[(pentylamino)carbonyl]-2-pyrrolidinyl}carbonyl)amino]-1-azetidinecarboxylate

Following the general method as outlined in Example 22, starting from1-(tert-butoxy-carbonyl)-4-methyleneproline, 1-isocyanatopentane, andtert-butyl 3-amino-1-azetidine-carboxylate the title compound wasobtained in 75% purity by LC/MS. MS(ESI+): m/z=395.2.

Example 236(3EZ,5S)-1-acetyl-5-[(4-acetyl-1-piperazinyl)carbonyl]-3-pyrrolidinoneO-(3,4-dichlorobenzyl)oxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, acetyl chloride, and 1-acetylpiperazine the title compound wasobtained in 85% purity by LC/MS. MS(ESI+): m/z=455.2.

Example 237(2S,4EZ)-N²-benzyl-4-(methoxyimino)-N¹-pentyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 1-isocyanatopentane, and benzylamine the title compound wasobtained in 100% purity by LC/MS. MS(ESI+): m/z=361.0.

Example 238(2S,4EZ)-1-acetyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(1-naphthyl-methyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, acetyl chloride, and 1-naphthylmethylamine the title compound wasobtained in 60% purity by LC/MS. MS(ESI+): m/z=484.2.

Example 239(2S,4EZ)-4-(tert-butoxyimino)-N-cyclopropyl-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and cyclopropylaminethe title compound was obtained in 75% purity by LC/MS. MS(ESI+):m/z=432.2.

Example 240(2S,4EZ)-4-{[(4-methoxybenzyl)oxy]imino}-1-(4-phenoxybenzoyl)-N-[2-(1H-pyrrol-1-yl)phenyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 4-phenoxybenzoyl chloride, and 2-(1H-pyrrol-1-yl)phenylamine thetitle compound was obtained in 55% purity by LC/MS. MS(ESI+): m/z=601.4.

Example 241(2S)—N-(1,3-benzodioxol-5-ylmethyl)-4-oxo-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-oxoproline, and1,3-benzodioxol-5-ylmethylamine the title compound was obtained in 71%purity by LC/MS. MS(ESI+): m/z=263.0.

Example 242(2S,4EZ)-N-(1,3-benzodioxol-5-ylmethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and1,3-benzodioxol-5-ylmethylamine the title compound was obtained in 63%purity by LC/MS. MS(ESI+): m/z=475.6.

Example 243(2S,4EZ)-N-(3,4-dimethoxybenzyl)-4-(ethoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and3,4-dimethoxybenzylamine the title compound was obtained in 41% purityby LC/MS. MS(ESI+): m/z=514.2.

Example 244(2S)-2-[(3-hydroxy-1-azetidinyl)carbonyl]-N-(3-methylphenyl)-4-oxo-1-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-oxoproline, 1-isocyanato-3-methylbenzene, and3-azetidinol the title compound was obtained in 73% purity by LC/MS.MS(ESI+): m/z=318.0.

Example 245(2S,4EZ)-4-[(benzyloxy)imino]-N-[(2RS)-2-hydroxy-2-phenethyl]-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and(1RS)-2-amino-1-phenylethanol the title compound was obtained in 55%purity by LC/MS. MS(ESI+): m/z=546.2.

Example 246(2S,4EZ)-4-[(allyloxy)imino]-N²-(3,4-dimethoxybenzyl)-N¹-(3-methoxy-phenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 1-isocyanato-3-methoxybenzene, and 3,4-dimethoxybenzylamine thetitle compound was obtained in 97% purity by LC/MS. MS(ESI+): m/z=483.2.

Example 247(2S,4EZ)-4-[(allyloxy)imino]-1-(4-cyanobenzoyl)-N-(2-methoxyethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-cyanobenzoyl chloride, and 2-methoxyethylamine the titlecompound was obtained in 44% purity by LC/MS. MS(ESI+): m/z=371.0.

Example 248(2S,4EZ)-N-benzyl-1-(methoxyacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and benzylamine the title compound wasobtained in 49% purity by LC/MS. MS(ESI+): m/z=426.2.

Example 249(2S,4EZ)-1-benzoyl-4-(chloromethylene)-N-(2-furylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 2-furylmethylamine the title compound wasobtained in 73% purity by LC/MS. MS(ESI+): m/z=345.6.

Example 250(2S)-1-acetyl-4-methylene-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline, acetyl chloride, and6-quinolinamine the title compound was obtained in 87% purity by LC/MS.MS(ESI+): m/z=296.0.

Example 251(2S,4EZ)-1-acetyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(2-furylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, acetyl chloride, and 2-furylmethylamine the title compound wasobtained in 199% purity by LC/MS. MS(ESI+): m/z=424.6.

Example 252(2S)—N¹-(3,5-dichlorophenyl)-4-methylene-N²-(6-quinolinyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxy-carbonyl)-4-methyleneproline,1,3-dichloro-5-isocyanatobenzene, and 6-quinolinamine the title compoundwas obtained in 65% purity by LC/MS. MS(ESI+): m/z=441.0.

Example 253(3EZ,5S)-1-(diphenylacetyl)-5-(1-piperidinylcarbonyl)-3-pyrrolidinoneO-(4-methoxybenzyl)oxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, diphenyl-acetyl chloride, and piperidine the title compound wasobtained in 87% purity by LC/MS. MS(ESI+): m/z=526.4.

Example 254(2S,4EZ)-4-(chloromethylene)-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 1-naphthylmethylamine the titlecompound was obtained in 75% purity by LC/MS. MS(ESI+): m/z=435.6.

Example 255(2S,4EZ)-4-[(allyloxy)imino]-N-benzoyl-2-(4-morpholinylcarbonyl)-1-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, benzoyl isocyanate, and morpholine the title compound was obtainedin 46% purity by LC/MS. MS(ESI+): m/z=401.2.

Example 256(2S,4EZ)-N¹-benzoyl-4-(chloromethylene)-N²-cyclopropyl-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, benzoyl isocyanate, and cyclopropylamine the title compound wasobtained in 76% purity by LC/MS. MS(ESI+): m/z=348.6.

Example: 257(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(methoxyacetyl)-N-(1-naphthylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, methoxyacetyl chloride, and 1-naphthylmethylamine the titlecompound was obtained in 91% purity by LC/MS. MS(ESI+): m/z=514.8.

Example 258(2S,4EZ)-1-benzoyl-N-benzyl-4-(chloromethylene)-N-methyl-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and N-benzyl-N-methylamine the title compoundwas obtained in 62% purity by LC/MS. MS(ESI+): m/z=369.4.

Example 259(2S)—N²-(2-furylmethyl)-N¹-(3-methoxyphenyl)-4-methylene-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline,1-isocyanato-3-methoxybenzene, and 2-furylmethylamine the title compoundwas obtained in 95% purity by LC/MS. MS(ESI+): m/z=356.0.

Example 260(3EZ,5S)-5-[(4-benzhydryl-1-piperazinylcarbonyl]-1-(phenoxyacetyl)-3-pyrrolidinoneO-ethyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 1-benzhydrylpiperazine the titlecompound was obtained in 67% purity by LC/MS. MS(ESI+): m/z=541.2.

Example 261 (3EZ,5S)-1-benzoyl-5-(4-morpholinylcarbonyl)-3-pyrrolidinoneO-(3,4-dichlorobenzyl)-oxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, benzoyl chloride, and morpholine the title compound was obtainedin 69% purity by LC/MS. MS(ESI+): m/z=476.2.

Example 262(2S)—N¹-(3-methoxyphenyl)-4-methylene-N²-(1-naphthylmethyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxy-carbonyl)-4-methyleneproline,1-isocyanato-3-methoxybenzene, and 1-naphthylmethyl-amine the titlecompound was obtained in 55% purity by LC/MS. MS(ESI+): m/z=416.3.

Example 263N²-(2-methoxyethyl)-4-methylene-N¹-(3-methylphenyl)-1,2-pyrrolidinedicarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline,1-isocyanato-3-methylbenzene, and 2-methoxyethylamine the title compoundwas obtained in 85% purity by LC/MS. MS(ESI+): m/z=318.0.

Example 264(2S,4EZ)-N-allyl-4-{[(4-methoxybenzyl)oxy]imino}-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, phenoxy-acetyl chloride, and allylamine the title compound wasobtained in 72% purity by LC/MS. MS(ESI+): m/z=438.2.

Example 265(2S,4EZ)-1-benzoyl-4-(cyanomethylene)-N-(1-naphthylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylicacid, benzoyl chloride, and 1-naphthylmethylamine the title compound wasobtained in 43% purity by LC/MS. MS(ESI+): m/z=396.0.

Example 266(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-[2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinaminethe title compound was obtained in 70% purity by LC/MS. MS(ESI+):m/z=621.2.

Example 267(2S,4EZ)-N-[2-(diethylamino)ethyl]-1-[4-(dimethylamino)butanoyl]-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylicacid, 4-(dimethylamino)butanoyl chloride, andN1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 100%purity by LC/MS. MS(ESI+): m/z=476.2.

Example 268(2S,4EZ)-4-[(allyloxy)imino]-1-[4-(dimethylamino)butanoyl]-N-(1-naphthylmethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 4-(dimethylamino)butanoyl chloride, and 1-naphthylmethylamine thetitle compound was obtained in 85% purity by LC/MS. MS(ESI+): m/z=437.2.

Example 269(2S,4EZ)-N-[2-(diethylamino)ethyl]-4-(ethoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, and N1,N1-diethyl-1,2-ethanediamine the title compound wasobtained in 70% purity by LC/MS. MS(ESI+): m/z=271.0.

Example 270(2S)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from1-(tert-butoxycarbonyl)-4-methyleneproline,2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinamine thetitle compound was obtained in 48% purity by LC/MS. MS(ESI+): m/z=446.2.

Example 271(2S,4EZ)-1-acryloyl-N-allyl-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, acryloyl chloride, and allylamine the title compound was obtainedin 81% purity by LC/MS. MS(ESI+): m/z=252.0.

Example 273 tert-butyl3-({[(2S,4EZ)-1-acetyl-4-benzylidenepyrrolidinyl]carbonyl}-amino)-1-azetidinecarboxylate

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, acetyl chloride, and tert-butyl 3-amino-1-azetidinecarboxylate thetitle compound was obtained in 81% purity by LC/MS. MS(ESI+): m/z=400.2.

Example 273(2S,4EZ)-4-[(allyloxy)imino]-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylicacid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinaminethe title compound was obtained in 67% purity by LC/MS. MS(ESI+):m/z=503.2.

Example 274(2S,4EZ)-4-(ethoxyimino)-N-(1-naphthylmethyl)-1-(phenoxyacetyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylicacid, phenoxyacetyl chloride, and 1-naphthylmethylamine the titlecompound was obtained in 85% purity by LC/MS. MS(ESI+): m/z=446.3.

Example 275(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 96.4%purity by HPLC. MS(ESI+): m/z=472.

Example 276(2S,4EZ)-1-([1,1′-biphenyl]-3-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenyl-ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-3-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 72%purity by HPLC. MS(ESI+): m/z=458.

Example 277(2S,4EZ)-1-(4-benzoylbenzoyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-benzoylbenzoic acid, and (1RS)-2-amino-1-phenylethanol, thetitle compound was obtained in 93% purity by HPLC. MS(ESI+): m/z=486.

Example 278(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-(3-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 3-phenoxybenzoic acid, and (1RS)-2-amino-1-phenylethanol, thetitle compound was obtained in 94% purity by HPLC. MS(ESI+): m/z=474.

Example 279(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-(2-phenoxybenzoyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2-phenoxybenzoic acid, and (1RS)-2-amino-1-phenylethanol, thetitle compound was obtained in 92% purity by HPLC. MS(ESI+): m/z=474.

Example 280(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1S)-2-amino-1-phenylethanol, the title compound was obtained in 98%purity by HPLC. MS(ESI+): m/z=472.

Example 281(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1R)-2-amino-1-phenylethanol, the title compound was obtained in 84%purity by HPLC. MS(ESI+): m/z=472.

Example 282(2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2-aminoethanol,the title compound was obtained in 75% purity by HPLC. MS(ESI+):m/z=396.

Example 283(2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-N-methyl-1-[(2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and2-(methylamino)ethanol, the title compound was obtained in 78% purity byHPLC. MS(ESI+): m/z=410.

Example 284(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S,2S,3R,4R)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and[(1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the titlecompound was obtained in 79% purity by HPLC. MS(ESI+): m/z=498.

Example 285(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(trans-4-hydroxycyclohexyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, andtrans-4-aminocyclohexanol, the title compound was obtained in 62% purityby HPLC. MS(ESI+): m/z=436.

Example 286(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and[(1R,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in65% purity by HPLC. MS(ESI+): m/z=450.

Example 287(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained in68% purity by HPLC. MS(ESI+): m/z=488.

Example 288(2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and(2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained in76% purity by HPLC. MS(ESI+): m/z=489.

Example 289(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained in78% purity by HPLC. MS(ESI+): m/z=524.

Example 290(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 63% purity by HPLC. MS(ESI+): m/z=474.

Example 291(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and4-[(RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 72% purity by HPLC. MS(ESI+): m/z=510.

Example 292(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1-hydroxycyclohexyl)-methyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and1-(aminomethyl)cyclohexanol, the title compound was obtained in 65%purity by HPLC. MS(ESI+): m/z=450.

Example 293(2S,4EZ)-N-[(1-hydroxycyclohexyl)methyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and 1-(aminomethyl)cyclohexanol, thetitle compound was obtained in 69% purity by HPLC. MS(ESI+): m/z=451.

Example 294(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1-hydroxycyclohexyl)methyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and1-(aminomethyl)cyclohexanol, the title compound was obtained in 66%purity by HPLC. MS(ESI+): m/z=486.

Example 295(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-(3,4-dihydroxy-phenyl)-2-hydroxyethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and4-[(1RS)-2-amino-1-hydroxyethyl]-1,2-benzenediol, the title compound wasobtained in 66% purity by HPLC. MS(ESI+): m/z=490.

Example 296(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(4-pyridinyl)benzoic acid, and (1S)-2-amino-1-phenylethanol, thetitle compound was obtained in 65% purity by HPLC. MS(ESI+): m/z=459.

Example 297(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and (1S)-2-amino-1-phenylethanol, thetitle compound was obtained in 73% purity by HPLC. MS(ESI+): m/z=459.

Example 298(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(2-pyridinyl)benzoic acid, and (1S)-2-amino-1-phenylethanol, thetitle compound was obtained in 69% purity by HPLC. MS(ESI+): m/z=459.

Example 299(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(2RS)-3-amino-1,2-propanediol, the title compound was obtained in 73%purity by HPLC. MS(ESI+): m/z=412.

Example 300(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(2RS)-3-amino-1,2-propanediol, the title compound was obtained in 64%purity by HPLC. MS(ESI+): m/z=448.

Example 301(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound wasobtained in 81% purity by HPLC. MS(ESI+): m/z=518.

Example 302(2S,4EZ)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxy-imino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and(2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound wasobtained in 63% purity by HPLC. MS(ESI+): m/z=519.

Example 303(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound wasobtained in 69% purity by HPLC. MS(ESI+): m/z=554.

Example 304(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and (2RS)-1-amino-2-propanol,the title compound was obtained in 82% purity by HPLC. MS(ESI+):m/z=396.

Example 305(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and (2RS)-1-amino-2-propanol,the title compound was obtained in 75% purity by HPLC. MS(ESI+):m/z=432.

Example 306(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(2naphthyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(1RS)-2-amino-1-(2-naphthyl)ethanol, the title compound was obtained in77% purity by HPLC. MS(ESI+): m/z=544.

Example 307(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was obtainedin 84% purity by HPLC. MS(ESI+): m/z=503.

Example 308(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(4-pyridinyl)benzoic acid, and(1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was obtainedin 89% purity by HPLC. MS(ESI+): m/z=504.

Example 309(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and(1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was obtainedin 72% purity by HPLC. MS(ESI+): m/z=504.

Example 310(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(2-pyridinyl)benzoic acid, and(1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was obtainedin 63% purity by HPLC. MS(ESI+): m/z=504.

Example 311(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was obtainedin 79% purity by HPLC. MS(ESI+): m/z=539.

Example 312(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, andN-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl)acetamide, the titlecompound was obtained in 79% purity by HPLC. MS(ESI+): m/z=545.

Example 313(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(4-pyridinyl)benzoic acid, andN-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl)acetamide, the titlecompound was obtained in 62% purity by HPLC. MS(ESI+): m/z=546.

Example 314(2S,4EZ)-N-[(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, andN-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl)acetamide, the titlecompound was obtained in 66% purity by HPLC. MS(ESI+): m/z=546.

Example 315(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, andN-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl)acetamide, the titlecompound was obtained in 62% purity by HPLC. MS(ESI+): m/z=581.

Example 316(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1R)-2-amino-1-phenylethanol, the title compound was obtained in 84%purity by HPLC. MS(ESI+): m/z=458.

Example 317(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(4-pyridinyl)benzoic acid, and (1R)-2-amino-1-phenylethanol, thetitle compound was obtained in 66% purity by HPLC. MS(ESI+): m/z=459.

Example 318(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and (1R)-2-amino-1-phenylethanol, thetitle compound was obtained in 76% purity by HPLC. MS(ESI+): m/z=459.

Example 319(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(2-pyridinyl)benzoic acid, and (1R)-2-amino-1-phenylethanol, thetitle compound was obtained in 65% purity by HPLC. MS(ESI+): m/z=459.

Example 320(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2R)-2-hydroxy-2-phenyl-ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(1R)-2-amino-1-phenylethanol, the title compound was obtained in 87%purity by HPLC. MS(ESI+): m/z=494.

Example 321(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(3-hydroxypropyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 3-amino-1-propanol, thetitle compound was obtained in 81% purity by HPLC. MS(ESI+): m/z=395.

Example 322(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-(3-hydroxypropyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and 3-amino-1-propanol, thetitle compound was obtained in 64% purity by HPLC. MS(ESI+): m/z=432.

Example 323(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 4-phenyl-4-piperidinol,the title compound was obtained in 74% purity by HPLC. MS(ESI+):m/z=498.

Example 324(3EZ,5S)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-1-[4-(4-pyridinyl)benzoyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(4-pyridinyl)benzoic acid, and 4-phenyl-4-piperidinol, the titlecompound was obtained in 78% purity by HPLC. MS(ESI+): m/z=499.

Example 325(3EZ,5S)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-1-[4-(3-pyridinyl)benzoyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and 4-phenyl-4-piperidinol, the titlecompound was obtained in 79% purity by HPLC. MS(ESI+): m/z=499.

Example 326(3EZ,5S)-1-([1,1′-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and 4-phenyl-4-piperidinol,the title compound was obtained in 84% purity by HPLC. MS(ESI+):m/z=534.

Example 327(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1S,2S)-2-aminocyclohexanol, the title compound was obtained in 84%purity by HPLC. MS(ESI+): m/z=436.

Example 328(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(1S,2S)-2-aminocyclohexanol, the title compound was obtained in 61%purity by HPLC. MS(ESI+): m/z=472.

Example 329(2S,4EZ)-N-benzyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-(benzylamino)ethanol,the title compound was obtained in 74% purity by HPLC. MS(ESI+):m/z=472.

Example 330(2S,4EZ)-N-benzyl-N-(2-hydroxyethyl)-4-(methoxyimino)-1-[4-(3-pyridinyl)-benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and 2-(benzylamino)ethanol, the titlecompound was obtained in 82% purity by HPLC. MS(ESI+): m/z=473.

Example 331(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{[(3RS)-3-hydroxypiperidinyl]-carbonyl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and (3RS)-3-piperidinol, thetitle compound was obtained in 78% purity by HPLC. MS(ESI+): m/z=422.

Example 332(3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-1-[4-(4-pyridinyl)-benzoyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(4-pyridinyl)benzoic acid, and (3RS)-3-piperidinol, the titlecompound was obtained in 91% purity by HPLC. MS(ESI+): m/z=423.

Example 333(3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-1-[4-(3-pyridinyl)-benzoyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and (3RS)-3-piperidinol, the titlecompound was obtained in 84% purity by HPLC. MS(ESI+): m/z=423.

Example 334(3EZ,5S)-1-([1,1′-biphenyl]-4-ylsulfonyl)-5-{[(3RS)-3-hydroxypiperidinyl]-carbonyl}-3-pyrrolidinoneO-methyl oxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and (3RS)-3-piperidinol, thetitle compound was obtained in 79% purity by HPLC. MS(ESI+): m/z=458.

Example 335(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1S,2S)-2-amino-1-phenyl-1,3-propanediol, the title compound wasobtained in 88% purity by HPLC. MS(ESI+): m/z=488.

Example 336(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(4-pyridinyl)benzoic acid, and(1S,2S)-2-amino-1-phenyl-1,3-propanediol, the title compound wasobtained in 64% purity by HPLC. MS(ESI+): m/z=489.

Example 337(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and(1S,2S)-2-amino-1-phenyl-1,3-propanediol, the title compound wasobtained in 93% purity by HPLC. MS(ESI+): m/z=489.

Example 338(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(1S,2S)-2-amino-1-phenyl-1,3-propanediol, the title compound wasobtained in 82% purity by HPLC. MS(ESI+): m/z=524.

Example 339(2S,4EZ)-N-(2-anilinoethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxy-imino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, andN¹-phenyl-1,2-ethanediamine, the title compound was obtained in 93%purity by HPLC. MS(ESI+): m/z=457.

Example 340(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(4-pyridinyl)benzoic acid, and N¹-phenyl-1,2-ethanediamine, thetitle compound was obtained in 85% purity by HPLC. MS(ESI+): m/z=458.

Example 341(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(3-pyridinyl)benzoic acid, and N¹-phenyl-1,2-ethanediamine, thetitle compound was obtained in 85% purity by HPLC. MS(ESI+): m/z=458.

Example 342(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 4-(2-pyridinyl)benzoic acid, and N¹-phenyl-1,2-ethanediamine, thetitle compound was obtained in 67% purity by HPLC. MS(ESI+): m/z=458.

Example 343(2S,4EZ)-N-(2-anilinoethyl)-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxy-imino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, andN¹-phenyl-1,2-ethanediamine, the title compound was obtained in 73%purity by HPLC. MS(ESI+): m/z=493.

Example 344(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-1-piperidinyl)-carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 4-piperidinol, the titlecompound was obtained in 86% purity by HPLC. MS(ESI+): m/z=422.

Example 345(3EZ,5S)-1-([1,1′-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy-1-piperidinyl)-carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and 4-piperidinol, the titlecompound was obtained in 68% purity by HPLC. MS(ESI+): m/z=458.

Example 346(2S,4EZ)-N-[(1S,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the titlecompound was obtained in 79% purity by HPLC. MS(ESI+): m/z=509.

Example 347(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 3-aminopropanamide, thetitle compound was obtained in 71% purity by HPLC. MS(ESI+): m/z=409.

Example 348(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and(1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the titlecompound was obtained in 83% purity by HPLC. MS(ESI+): m/z=509.

Example 349(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(4-hydroxybutyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 4-amino-1-butanol, thetitle compound was obtained in 68% purity by HPLC. MS(ESI+): m/z=410.

Example 350(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-(4-hydroxybutyl)-4-(methoxy-imino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and 4-amino-1-butanol, thetitle compound was obtained in 78% purity by HPLC. MS(ESI+): m/z=446.

Example 351(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1R,2R)-2-(hydroxymethyl)-cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and[(1R,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in40% purity by HPLC. MS(ESI+): m/z=486.

Example 352(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1R,2S,3R,4S)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and[(1S,2R,3S,4R)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the titlecompound was obtained in 58% purity by HPLC. MS(ESI+): m/z=498.

Example 353(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1R,2S)-2-(hydroxymethyl)-cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-sulfonyl chloride, and[(1S,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in41% purity by HPLC. MS(ESI+): m/z=486.

Example 354 (2S,4E and4Z)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compounds were obtained as amixture of E/Z-isomers of the oxime functionality. Separation of theisomers by flash chromatography yielded(2S,4E)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamidein 98.9% purity and(2S,4Z)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamidein 99.9% purity by HPLC. MS(ESI+): m/z=472.

Example 355 (2S,4E and4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1S)-2-amino-1-phenylethanol, the title compounds were obtained as amixture of E/Z-isomers of the oxime functionality. Separation of theisomers by flash chromatography yielded(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamidein 98.9% purity and(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamidein 99.8% purity by HPLC. MS(ESI+): m/z=472.

Example 356 (2S,4E and4Z)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1R)-2-amino-1-phenylethanol, the title compounds were obtained as amixture of E/Z-isomers of the oxime functionality. Separation of theisomers by flash chromatography yielded(2S,4E)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamidein 99.7% purity and(2S,4Z)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamidein 99.7% purity by HPLC. MS(ESI+): m/z=472.

Example 357(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1R,2S)-2-(hydroxymethyl)-cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and[(1S,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in63% purity by HPLC. MS(ESI+): m/z=450.

Example 358(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[2-hydroxy-1-(hydroxymethyl)-ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-amino-1,3-propanediol,the title compound was obtained in 61% purity by HPLC. MS(ESI+):m/z=412.

Example 359(2S,4EZ)-N-[(1S,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the titlecompound was obtained in 68% purity by HPLC. MS(ESI+): m/z=473.

Example 360(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the titlecompound was obtained in 78% purity by HPLC. MS(ESI+): m/z=473.

Example 361(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenyl-ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1S)-2-amino-1-phenylethanol, the title compound was obtained in 87,%purity by HPLC. MS(ESI+): m/z=458.

Example 362(2RS)-3-({[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-pyrrolidinyl]carbonyl}amino)-2-hydroxypropanoicacid

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(2RS)-3-amino-2-hydroxypropanoic acid, the title compound was obtainedin 44% purity by HPLC. MS(ESI+): m/z=426.

Example 363(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1S,2R)-2-aminocyclohexanecarboxamide, the title compound was obtainedin 89% purity by HPLC. MS(ESI+): m/z=463.

Example 364(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1RS)-2-hydroxy-1-methyl-ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and (2RS)-2-amino-1-propanol,the title compound was obtained in 81% purity by HPLC. MS(ESI+):m/z=396.

Example 365(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, the title compoundwas obtained in 70% purity by HPLC. MS(ESI+): m/z=533.

Example 3664-({[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]carbonyl}amino)butanoicacid

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 4-aminobutanoic acid, thetitle compound was obtained in 57% purity by HPLC. MS(ESI+): m/z=424.

Example 367(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and(1S)-2-amino-1-phenylethanol, the title compound was obtained in 90%purity by HPLC. MS(ESI+): m/z=488.

Example 368(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(2-naphthyl)ethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-(2-naphthyl)ethanol, the title compound was obtained in67% purity by HPLC. MS(ESI+): m/z=538.

Example 369(2S,4EZ)-N-[(1RS)-2-hydroxy-1-methylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(2RS)-2-amino-1-propanol, the title compound was obtained in 88% purityby HPLC. MS(ESI+): m/z=410.

Example 370(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, the title compoundwas obtained in 74% purity by HPLC. MS(ESI+): m/z=547.

Example 371(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and(1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, the title compoundwas obtained in 61% purity by HPLC. MS(ESI+): m/z=563.

Example 372(3EZ,5S)-5-[(4-hydroxy-1-piperidinyl)carbonyl]-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 4-piperidinol, thetitle compound was obtained in 86% purity by HPLC. MS(ESI+): m/z=436.

Example 373(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the titlecompound was obtained in 55% purity by HPLC. MS(ESI+): m/z=487.

Example 374(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 82%purity by HPLC. MS(ESI+): m/z=488.

Example 375(2S,4EZ)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(2RS)-1-amino-2-propanol, the title compound was obtained in 90% purityby HPLC. MS(ESI+): m/z=410.

Example 376(2S,4EZ)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-1-[(2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(2RS)-3-amino-1,2-propanediol, the title compound was obtained in 67%purity by HPLC. MS(ESI+): m/z=426.

Example 377(2S,4EZ)-N-(3-hydroxypropyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and3-amino-1-propanol, the title compound was obtained in 90% purity byHPLC. MS(ESI+): m/z=410.

Example 378(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-aminoacetamide, thetitle compound was obtained in 82% purity by HPLC. MS(ESI+): m/z 395.

Example 379(2S,4EZ)-N-(2-amino-2-oxoethyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2-aminoacetamide,the title compound was obtained in 92% purity by HPLC. MS(ESI+):m/z=409.

Example 380(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 88% purity by HPLC. MS(ESI+): m/z=504.

Example 381(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2R,3S,4R)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and[(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the titlecompound was obtained in 64% purity by HPLC. MS(ESI+): m/z=462.

Example 382(2S,4EZ)-N-[(1R,2S,3R,4S)-3-(hydroxymethylbicyclo[2.2.1]hept-2-yl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and[(1S,2R,3S,4R)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the titlecompound was obtained in 56% purity by HPLC. MS(ESI+): m/z=492.

Example 383(2S,4EZ)-N-(trans-4-hydroxycyclohexyl)-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, andtrans-4-aminocyclohexanol, the title compound was obtained in 61% purityby HPLC. MS(ESI+): m/z=466.

Example 384(2S,4EZ)-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and[(1R,2R)-2-aminocyclohexyl]methanol the title compound was obtained in68% purity by HPLC. MS(ESI+): m/z=480.

Example 385(2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained in80% purity by HPLC. MS(ESI+): m/z=502.

Example 386(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxy-imino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 76% purity by HPLC. MS(ESI+): m/z=488.

Example 387(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxy-imino)-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 90% purity by HPLC. MS(ESI+): m/z=504.

Example 388(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and4-[(1RS)-2-amino-1-hydroxyethyl]-2-methoxyphenol, the title compound wasobtained in 67% purity by HPLC. MS(ESI+): m/z=518.

Example 389(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and4-[(1RS)-2-amino-1-hydroxyethyl]-2-methoxyphenol, the title compound wasobtained in 87% purity by HPLC. MS(ESI+): m/z=534.

Example 390(2S,4EZ)-N-[(2RS)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and4-[(1RS)-2-amino-1-hydroxyethyl]-1,2-benzenediol, the title compound wasobtained in 69% purity by HPLC. MS(ESI+): m/z=520.

Example 391(2R,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenyl-ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2R,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 90%purity by HPLC. MS(ESI+): m/z=456.

Example 392(2R,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2R,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 94%purity by HPLC. MS(ESI+): m/z=472.

Example 393(2S,4EZ)-1-[(2′-cyano[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-cyano[1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 86%purity by HPLC. MS(ESI+): m/z=483.

Example 394(2S,4EZ)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 3′,4′-dichloro[1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 89%purity by HPLC. MS(ESI+): m/z=527.

Example 395(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 95%purity by HPLC. MS(ESI+): m/z=486.

Example 396(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and(1RS)-2-amino-1-phenylethanol, the title compound was obtained in 83%purity by HPLC. MS(ESI+): m/z=486.

Example 397(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxy-imino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 70% purity by HPLC. MS(ESI+): m/z=488.

Example 398(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxy-imino)-1-[(2′-cyano[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-cyano[1,1′-biphenyl]-4-carboxylic acid, and3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 86% purity by HPLC. MS(ESI+): m/z=499.

Example 399(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxy-imino)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 3′,4′-dichloro[1,1′-biphenyl]-4-carboxylic acid, and3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 91% purity by HPLC. MS(ESI+): m/z=543.

Example 400(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxy-imino)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 87% purity by HPLC. MS(ESI+): m/z=502.

Example 401(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxy-imino)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 91% purity by HPLC. MS(ESI+): m/z=502.

Example 402(2S,4EZ)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 3′,4′-dichloro[1,1′-biphenyl]-4-carboxylic acid, and4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 86% purity by HPLC. MS(ESI+): m/z=543.

Example 403(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 89% purity by HPLC. MS(ESI+): m/z=502.

Example 404(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtainedin 90% purity by HPLC. MS(ESI+): m/z=502.

Example 405(2S,4EZ)-1-[(2′,6′-dimethyl[111′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and(2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound wasobtained in 87% purity by HPLC. MS(ESI+): m/z=546.

Example 406(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and(2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound wasobtained in 77% purity by HPLC. MS(ESI+): m/z=546.

Example 407(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and2-aminoacetamide, the title compound was obtained in 88% purity by HPLC.MS(ESI+): m/z=423.

Example 408(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and2-aminoacetamide, the title compound was obtained in 85% purity by HPLC.MS(ESI+): m/z=423.

Example 409(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and3-aminopropionamide, the title compound was obtained in 87% purity byHPLC. MS(ESI+): m/z=437.

Example 410(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and3-aminopropionamide, the title compound was obtained in 87% purity byHPLC. MS(ESI+): -m/z=437.

Example 411(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and2-amino-1,3-propanediol, the title compound was obtained in 70% purityby HPLC. MS(ESI+): m/z=440.

Example 412(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and2-amino-1,3-propanediol, the title compound was obtained in 68% purityby HPLC. MS(ESI+): m/z=440.

Example 413(2S,4EZ)-1-[(2′-cyano[1,1′-biphenyl]-4-yl)carbonyl]-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-cyano[1,1′-biphenyl]-4-carboxylic acid, and[(1R,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in78% purity by HPLC. MS(ESI+): m/z=475.

Example 414(3EZ,5S)-5-(3,4-dihydro-2(1H)-isoquinolinylcarbonyl)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and1,2,3,4-tetrahydroisoquinoline, the title compound was obtained in 77%purity by HPLC. MS(ESI+): m/z=482.

Example 415(2S,4EZ)-N-[(1R)-2-hydroxy-1-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(2R)-2-amino-2-phenylethanol, the title compound was obtained in 91%purity by HPLC. MS(ESI+): m/z=472.

Example 416(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and4-(2-aminoethyl)phenol, the title compound was obtained in 87% purity byHPLC. MS(ESI+): m/z=486.

Example 417(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and4-(2-aminoethyl)phenol, the title compound was obtained in 83% purity byHPLC. MS(ESI+): m/z=486.

Example 418(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and3-(2-aminoethyl)phenol, the title compound was obtained in 81% purity byHPLC. MS(ESI+): m/z=486.

Example 419(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and3-(2-aminoethyl)phenol, the title compound was obtained in 89% purity byHPLC. MS(ESI+): m/z=486.

Example 420(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(1R,2S)-2-hydroxy-1,2-diphenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and(1S,2R)-2-amino-1,2-diphenylethanol, the title compound was obtained in73% purity by HPLC. MS(ESI+): m/z=562.

Example 421(2RS)-2-[({(2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]pyrrolidinyl}carbonyl)amino]-3-phenylpropanoicacid

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and DL-phenylalanine,the title compound was obtained in 62% purity by HPLC. MS(ESI+):m/z=500.

Example 422(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and(1S,2R)-2-aminocyclohexanecarboxamide, the title compound was obtainedin 92% purity by HPLC. MS(ESI+): m/z=491.

Example 423(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and(1S,2R)-2-aminocyclohexanecarboxamide, the title compound was obtainedin 91% purity by HPLC. MS(ESI+): m/z=491.

Example 4244′-{[(2S,4EZ)-2-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-4-(methoxyimino)pyrrolidinyl]carbonyl}[1,1′-biphenyl]-2-carbonitrile

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-cyano[1,1′-biphenyl]-4-carboxylic acid, and2-(1-piperazinyl)ethanol, the title compound was obtained in 89% purityby HPLC. MS(ESI+): m/z=476.

Example 425(3EZ,5S)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 3′,4′-dichloro[1,1′-biphenyl]-4-carboxylic acid, and2-(1-piperazinyl)ethanol, the title compound was obtained in 86% purityby HPLC. MS(ESI+): m/z=520.

Example 426(3EZ,5S)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and2-(1-piperazinyl)ethanol, the title compound was obtained in 79%.purityby HPLC. MS(ESI+): m/z=479.

Example 427(3EZ,5S)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and2-(1-piperazinyl)ethanol, the title compound was obtained in 86% purityby HPLC. MS(ESI+): m/z=479.

Example 428(3EZ,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-({4-[4-(trifluoromethyl)phenyl]-1-piperazinyl}carbonyl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and1-[4-(trifluoromethyl)phenyl]piperazine, the title compound was obtainedin 89% purity by HPLC. MS(ESI+): m/z=565.

Example 429(3EZ,5S)-1-[(2′-methyl[,1′-biphenyl]-4-yl)carbonyl]-5-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}carbonyl)-3-pyrrolidinoneO-methyloxime

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and1-[3-(trifluoromethyl)phenyl]piperazine, the title compound was obtainedin 88% purity by HPLC. MS(ESI+): m/z=565.

Example 430(2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and ammonia (0.5M indioxane), the title compound was obtained in 88% purity by HPLC.MS(ESI+): m/z=352.

Example 431(2S,4EZ)-4-(methoxyimino)-N-methyl-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and methylamine (2M inmethanol), the title compound was obtained in 96% purity by HPLC.MS(ESI+): m/z=366.

Example 432(2S,4EZ)-4-(methoxyimino)-N,N-dimethyl-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and dimethylamine(5.6M in ethanol), the title compound was obtained in 94% purity byHPLC. MS(ESI+): m/z=380.

Example 433(2S,4EZ)-N-[(3R)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1R)-3-amino-1-phenyl-1-propanol, the title compound was obtained in 94%purity by HPLC. MS(ESI+): m/z=486.

Example 434(2S,4EZ)-N-[(3S)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1S)-3-amino-1-phenyl-1-propanol, the title compound was obtained in 91%purity by HPLC. MS(ESI+): m/z=486.

Example 435(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(3R)-3-hydroxy-3-phenyl-propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1R)-3-amino-1-phenyl-1-propanol, the title compound was obtained in 94%purity by HPLC. MS(ESI+): m/z=472.

Example 436(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(3S)-3-hydroxy-3-phenyl-propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1S)-3-amino-1-phenyl-1-propanol, the title compound was obtained in 93%purity by HPLC. MS(ESI+): m/z=472.

Example 437(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-{[2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid, and(1S)-2-amino-1-phenylethanol, the title compound was obtained in 87%purity by HPLC. MS(ESI+): m/z=526.

Example 438(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-{[2′-chloro[1,1′-biphenyl]-4-yl]carbonyl}-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-chloro[1,1′-biphenyl]-4-carboxylic acid, and(1S)-2-amino-1-phenylethanol, the title compound was obtained in 89%purity by HPLC. MS(ESI+): m/z=492.

Example 439(2S,4EZ)-N-(2-hydroxyphenyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2-aminophenol, thetitle compound was obtained in 88% purity by HPLC. MS(ESI+): m/z=444.

Example 440(2S,4EZ)-N-[2-(hydroxymethyl)phenyl]-4-(methoxyimino)-1-[(2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and(2-aminophenyl)methanol, the title compound was obtained in 86% purityby HPLC. MS(ESI+): m/z=458.

Example 441(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2-methyl[1,1′-biphenyl]-4-carboxylic acid, and(1S)-2-amino-1-phenylethanol, the title compound was obtained in 95%purity by HPLC. MS(ESI+): m/z=472.

Example 442 (2S,4E and4Z)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, [1,1′-biphenyl]-4-carbonyl chloride, and(1S)-2-amino-1-phenylethanol, the title compounds were obtained as amixture of E/Z-isomers of the oxime functionality. Separation of theisomers by flash chromatography yielded(2S,4E)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamidein 98.8% purity and(2S,4Z)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamidein 97.4% purity by HPLC. MS(ESI+): m/z=458.

Example 443(2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-phenylethyl)-2-pyrrolidinecarboxamide

Following the general method as outlined in Example 22, starting from(2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylicacid, 2-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2-phenylethanamine,the title compound was obtained in 89% purity by HPLC. MS(ESI+):m/z=456.

Example 444 Preparation of a Pharmaceutical Formulation

The following formulation examples illustrate representativepharmaceutical compositions according to the present invention being notrestricted thereto.

Formulation 1—Tablets

A pyrrolidine compound of formula I is admixed as a dry powder with adry gelatin binder in an approximate 1:2 weight ration. A minor amountof magnesium stearate is added as a lubricant. The mixture is formedinto 240-270 mg tablets (80-90 mg of active pyrrolidine compound pertablet) in a tablet press.

Formulation 2—Capsules

A pyrrolidine compound of formula I is admixed as a dry powder with astarch diluent in an approximate 1:1 weight ratio. The mixture is filledinto 250 mg capsules (125 mg of active pyrrolidine compound percapsule).

Formulation 3—Liquid

A pyrrolidine compound of formula I (1250 mg), sucrose (1.75 g) andxanthan gum (4 mg) are blended, passed through a No. 0.10 mesh U.S.sieve, and then mixed with a previously prepared solution ofmicrocrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50mg) in water. Sodium benzoate (10 mg), flavor, and color are dilutedwith water and added with stirring. Sufficient water is then added toproduce a total volume of 5 mL.

Formulation 4—Tablets

A pyrrolidine compound of formula I is admixed as a dry powder with adry gelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into450-900 mg tablets (150-300 mg of active pyrrolidine compound) in atablet press.

Formulation 5—Injection

A pyrrolidine compound of formula I is dissolved in a buffered sterilesaline injectable aqueous medium to a concentration of approximately 5mg/ml.

Example 445 Biological Assays a) In Vitro Binding Assay (SPA)

Membranes from HEK293EBNA cells expressing the hOT receptor wereresuspended in buffer containing 50 mM Tris-HCl, pH 7.4, 5 mM MgCl2 and0.1% BSA (w/v). The membranes (2-4 μg) were mixed with 0.1 mg wheat-germaglutinin (WGA) SPA bead (type A) and increasing concentrations of[¹²⁵I]-OVTA (for saturation binding experiments) or 0.2 nM [¹²⁵I]-OVTA(for competition binding experiments). Non specific binding wasdeter-mined in the presence of, 1 μM Oxytocin. The total assay volumewas 100 μl. The plates were incubated at room temperature for 30 min andcounted on a Mibrobeta plate counter. The competition binding data wereanalysed using the iterative, nonlinear, curve-fitting program, Prism.

b) Biological Results—Discussion

The binding affinities to the oxytocin receptor of the pyrrolidinederivatives claimed in the formula I were assessed using the abovedescribed in vitro biological assay. Representative values for someexample compounds are given in Table 1 below. The values refer to thebinding capacity of the example compounds according to formula I to theOxytocin receptor. From the values shown in Table 1 it can be derivedthat said test compounds according to formula I do show a significantbinding to the Oxytocin receptor.

TABLE 1 Binding affinity human OT-R Structure IUPAC-Name IC₅₀ (μM)

(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide0.13

(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide0.07

(3Z,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime 0.63

(2S,4Z)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide0.35

(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-(3-phenoxybenzoyl)-2-pyrrolidinecarboxamide2.3

(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide0.54

(2S,4EZ)-1-[(2′-chloro[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide0.17

(2S,4EZ)-N-(3-hydroxypropyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide0.37

(3EZ,5S)-5-[(4-hydroxy-1-piperidinyl)carbonyl]-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-3-pyrrolidinoneO-methyloxime 0.30

(2S,4EZ)-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide0.55

According to a preferred embodiment, the compounds display bindingaffinities (K_(i) (μM)) of less 0.40 μM, more preferred of less than 0.1μM.

c) Functional Assay No. 1: Inhibition of Ca²⁺-Mobilization by FLIPR

Preparing the plates: FLIPR-plates were pre-coated with PLL 10μg/ml+0.1% gelatine for 30 min up to 2 days at 37° C. (for HEK-cells).The cells were plated out into 96-well plates (60000 cells/well).

Labelling with fluo-4: 50 kg fluo-4 were dissolved in 20 μl pluronicacid (20% in DMSO). The dissolved fluo-4 was then diluted in 10 mlDMEM-F12 medium without FCS. The medium was removed from the plates,followed by one wash with DMEM-F12 medium. Now, 100 μl of the DMEM-F12medium containing fluo-4 were added and the cells incubated for 1-1.5 h(CHO-cells), and 1.5-2 h (HEK-cells).

Buffer: 145 mM NaCl, 5 mM KCl, 1 mM MgCl₂, 10 mM Hepes, 10 mM Glucose,EGTA. Adjust to pH 7.4.

Preparation of agonists and antagonists: A minimum of 80 μl/well ofagonists and antagonists (5×) in the above buffer (1×) were prepared(96-well plates).

The activities of the pyrrolidine derivatives according to formula Iwere assessed using the above described in vitro biological assay.Representative values for some example compounds are given in Table 2below. The values refer to the capacity of the example compoundsaccording to formula I to effectively antagonize oxytocin-inducedintracellular Ca²⁺-mobilization mediated by the Oxytocin receptor. Fromthe values shown in Table 2 it can be derived that said example testcompounds according to formula I do exhibit a significant activity asOxytocin receptor antagonists.

TABLE 2 Inhibition of Ca²⁺- mobilization, hOT-R, Structure IUPAC NameIC₅₀ (μM)

(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide0.07

(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide0.03

(2S,4EZ)-N-[(3R)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide0.32

(3Z,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime 0.4

(2S,4Z)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide0.65

d) Functional Assay No. 2: Inhibition of IP3-Synthesis in HEK/EBNA-OTRCells

Stimulation of the cells: HEK/EBNA OTR (rat or human) cells were platedout into costar 12-well plates, and equilibrated for 15-24 h with[³H]-inositol in medium without inositol supplement, with 1% FCS (0.5ml/well). 4 μCi/ml were used. After this, the medium containing thelabel was aspirated. Then was added DMEM (without FCS, inositol), 20 mMHepes, 1 mg/ml BSA containing 10 mM LiCl (freshly prepared), for 10-15min at 37° C. The agonists and antagonists were added for the timerequired (15-45 min), followed by aspiration of the medium. The reactionwas stopped with 1 ml STOP-solution (0.4 M perchloric acid), and let sitfor 5-10 min at RT (not longer). Then, 0.8 ml were transferred intotubes containing 0.4 ml of neutralizing solution (0.72 M KOH/0.6MKHCO₃), and the tubes vortexed and kept in the cold at least for 2 h. Atthis stage, samples could be kept over a prolonged period of time.

Separation of IP's: The samples were spun in a table top centrifuge at3000-4000 rpm for 15 min. 1 ml of the supernatant was transferred to newtubes containing 2.5 ml H₂O. Packed resin (0.8 ml) was equilibrated with20 ml H₂O, and the whole samples poured onto the columns. To discardfree inositol, two washes with 10 ml H₂O were carried out.

Elution of total IP's: The elution was achieved using 3 ml 1M ammoniumformate/0.1M formic acid. The eluant was collected in scintillationcounting tubes, followed by addition of 7 ml of scintillation liquid.Mixing and counting concluded the operation.

The activities of the pyrrolidine derivatives claimed in the formula Iwere assessed using the above described in vitro biological assay.Representative values for some example compounds are given in Table 3below. The values refer to the capacity of the example compoundsaccording to formula I to effectively antagonize oxytocin-inducedIP3-synthesis mediated by the Oxytocin receptor. From the values shownin Table 3 it can be derived that said example test compounds accordingto formula I do exhibit a significant activity as Oxytocin receptorantagonists.

TABLE 3 Inhibition of IP3- synthesis, ratOT-R Structure IUPAC Name IC₅₀(μM)

(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide0.33

(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide0.03

(2S,4Z)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide0.35

e) In Vivo Model for Inhibition of Uterine Contractions

Non-pregnant Charles River CD(SD) BR female rats (9-10 weeks old,200-250 g) were treated at 18 and 24 hours before the experiment with250 μg/kg, i.p. diethylstilbestrol (DES). For the assay, the animal wasanaesthetised by urethane (1.75 g/kg, i.p.) and placed on anhomeothermic operating table. The trachea was isolated and cannulatedwith a suitable polyethylene (PE) tubing. A midline incision at thehypogastrium level was made and one uterine horn exposed, its cephalicend cannulated with a PE240 tubing and, after filling the internalcavity with 0.2 ml of sterile physiological saline, connected to a“Gemini” amplifying/recording system via a P23ID Gould Statham pressuretransducer. For the i.v. route of administration of the test compounds,one jugular vein was isolated and cannulated with a PE60 tubingconnected to a butterfly needle to allow the administration by adispensing syringe. In the case of intraduodenal administration of thetest compounds, the duodenum was isolated and similarly cannulatedthrough a small incision in its wall. One carotid artery was alsoisolated and cannulated with PE60 catheter and connected to a suitablesyringe for blood sample collection (see below). After a stabilizationperiod, the same dose of oxytocin was repeatedly injected intravenouslyat 30-min intervals. When comparable contractile responses of the uterusto the selected dose of oxytocin were obtained, the dose of the test orreference compound was administered. Further injections of the same doseof oxytocin were then made for a suitable time after treatment to assessinhibitory effects of the compounds under study. The contractileresponse of the uterus to oxytocin was quantified by measuring theintrauterine pressure and the number of contractions. The effect of thereference and test compounds were evaluated by comparing pre- andpost-treatment pressure values. In addition, at 2, 30, 90 and 210minutes after test compound administration, a 0.5-ml blood sample waswithdrawn from the cannulated carotid artery of each experimentalanimal. Plasma was obtained by standard laboratory procedure and theresulting samples were stored at −20° C.

The activities of the pyrrolidine derivatives claimed in the formula Iwere assessed using the above described in vivo biological assay.Representative values for one example compound are given in Table 4below. The values refer to the capacity of the example compoundaccording to formula I to effectively antagonize oxytocin-induceduterine contractions in the rat. From the values shown in Table 4 it canbe derived that said example test compound according to formula I doesexhibit a significant activity as tocolytic, i.e. uterine-relaxing,agent.

TABLE 4 Route of % Reduction of administration/ Uterine Dose StructureIUPAC Name Vehicle Contraction (mg/kg)

(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamideintravenous;PEG 400/saline50:50;5 ml/kg infusion −23.8 ± 4.1−27.6 ±4.6−50.4 ± 5.8−65.6 ± 6.4 −76.5 ± 4.24   0.3 1 31030

1. Pyrrolidine compounds according to formula I

as well as its geometrical isomers, its optically active forms asenantiomers, diastereomers and its racemate forms, as well aspharmaceutically acceptable salts thereof, wherein X is selected fromthe group consisting of CR⁶R⁷, NOR⁶, NNR⁶R⁷; m is an integer selectedfrom the group consisting of 0, 1, 2 and 3; A is selected from the groupconsisting of —SO₂—, —SO₂NH—, —CH₂—, B is either a group —C═O)—NR⁸R⁹ orrepresents a heterocyclic residue having the formula

wherein Q is NR¹⁰, O or S; n is an integer selected of 0, 1 or 2; Y, Zand E form together with the 2 carbons to which they are attached a 5-6membered aryl or heteroaryl ring, R¹ is selected from the groupconsisting of unsubstituted or substituted C₁-C₆-alkyl, unsubstituted orsubstituted C₂-C₆-alkenyl, unsubstituted or substituted C₂-C₆-alkynyl;unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted saturated or unsaturated3-8-membered cycloalkyl, unsubstituted or substituted C₁-C₆-alkylheteroaryl, said cycloalkyl or aryl or heteroaryl groups may be fusedwith 1-2 further cycloalkyl or aryl or heteroaryl group; R², R³, R⁴ andR⁵ are independently selected from each other from the group consistingof hydrogen, halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy; R⁶ and R⁷ areindependently selected from the group consisting of hydrogen,unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substitutedC₂-C₆ alkenyl, unsubstituted or substituted C₂-C₆ alkynyl, unsubstitutedor substituted alkoxy, unsubstituted or substituted thioalkoxy, halogen,cyano, nitro, acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted orsubstituted saturated or unsaturated 3-8-membered cycloalkyl which maycontain 1 to 3 heteroatoms selected of N, O, S, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted C₁-C₆-alkyl aryl, unsubstituted or substitutedC₁-C₆-alkyl heteroaryl; R⁸, R⁹ and R¹⁰ are independently selected fromthe group comprising or consisting of hydrogen, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆ alkenyl,unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or substitutedsaturated or unsaturated 3-8-membered cycloalkyl which may contain 1 to3 heteroatoms selected of N, O, S, unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl, or each pair R⁶, R⁷ and/or R⁸,R⁹ could form together with the N atom to which they are attached a 3-8membered substituted or unsubstituted, saturated or unsaturatedhetero-cyclic ring which may contain 1-2 further heteroatoms selectedfrom N, S and O and which is optionally fused with an aryl, heteroarylor 3-8 membered saturated or unsaturated cycloalkyl ring; R¹¹ isselected from the group comprising or consisting of hydrogen,unsubstituted or substituted C₁-C₆-alkyl, unsubstituted or substitutedalkenyl, unsubstituted or substituted alkynyl, hydroxy, mercapto,alkoxy, thioalkoxy, aryl, heteroaryl, halogen, nitro, cyano, acyl,acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, sulfonyl, sulfoxy,carboxyl, primary, secondary or tertiary amino groups or quaternaryammonium moieties, unsubstituted or substituted saturated or unsaturated3-8-membered cyclo-alkyl.
 2. A pyrrolidine compound according to claim1, wherein B is a group —(C═O)—NHR⁹, in which R⁹ is selected from thegroup consisting of unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or substitutedC₂-C₆ alkynyl, unsubstituted or substituted saturated or unsaturated3-6-membered cycloalkyl which optionally contains a N atom,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted C₁-C₂-alkyl aryl, unsubstitutedor substituted C₁-C₂-alkyl heteroaryl.
 3. A pyrrolidine compoundaccording to claim 1, wherein B is a fused heterocycle of the formula


4. A pyrrolidine compound according to claim 2, wherein R⁹ is aheteroaryl selected from pyridyl, pyrrolyl, furyl, thienyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl,benzo-furyl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl,benzotriazolyl, isobenzo-thienyl, 2,1,3-benzothiadiazolyl,2,1,3-benzoxadiazolyl, benzodioxolyl, indolyl, isoindolyl, 3H-indolyl,benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl,quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl,napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl,pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl,5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl,pteridinyl, carbazolyl, xanthenyl, acridinyl or benzoquinolyl andwhereby said heteroaryl could be fused with a 3-8-membered cycloalkylcontaining optionally 1-3 heteroatoms selected from N, O, S.
 5. Apyrrolidine compound according to claim 1, wherein X is NOR⁶, and R⁶ isselected from the group consisting of H, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₂-C₆ alkenyl, unsubstitutedor substituted C₂-C₆ alkynyl, unsubstituted or substituted acyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted saturated or unsaturated3-8-membered cycloalkyl, unsubstituted or substituted C₁-C₆-alkyl aryl,unsubstituted or substituted C₁-C₆-alkyl heteroaryl, said cycloalkyl oraryl or heteroaryl groups may be fused with 1-2 further cycloalkyl oraryl or heteroaryl groups.
 6. A pyrrolidine compound according to claim5, wherein R⁶ is H, CH₃, unsubstituted or substituted CH₂-phenyl orallyl, preferably H or methyl.
 7. A pyrrolidine compound according toclaim 1, wherein X is CHR⁶, R⁶ is selected from the group consisting ofhalogen, cyano, unsubstituted or substituted C₃-C₆ alkyl, unsubstitutedor substituted C₂-C₆ alkenyl, unsubstituted or substituted C₂-C₆alkynyl, unsubstituted or substituted alkoxy, unsubstituted orsubstituted thioalkoxy, nitro, acyl, alkoxycarbonyl, aminocarbonyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted saturated or unsaturated3-8-membered cycloalkyl, unsubstituted or substituted C₁-C₆-alkyl aryl,unsubstituted or substituted C₁-C₆-alkyl heteroaryl, said cycloalkyl oraryl or heteroaryl groups may be fused with 1-2 further cycloalkyl oraryl or heteroaryl groups.
 8. A pyrrolidine compound according to claim7, wherein R⁶ is selected from the group consisting of halogen, cyano,C₃-C₆ alkyl or an unsubstituted or substituted phenyl group.
 9. Apyrrolidine compound according to claim 1, wherein A is —(C═O)—, or—(C═O)—NH—, or —SO₂—.
 10. A pyrrolidine compound according to claim 1,wherein R¹ is an C₁-C₆-alkyl, C₂-C₆-alkenyl, unsubstituted orsubstituted C₂-C₆-alkynyl, aryl, heteroaryl, saturated or unsaturated3-8-membered cycloalkyl, C₁-C₆-alkyl aryl, C₁-C₆-alkyl heteroaryl.
 11. Apyrrolidine compound according to claim 10, wherein R¹ is an C₁-C₆-alkylor aryl group.
 12. A pyrrolidine compound according to claim 12, whereinR¹ is biphenyl.
 13. A pyrrolidine compound according to claim 1,selected from the following group:(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxy-imino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-furylmethyl)-2-pyrrolidinecarboxamide(2S,4EZ)-4-(cyanomethylene)-N-(2-furylmethyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-(2-furylmethyl)-4-(methoxyimino)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)-carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-4-(cyanomethylene)-1-(diphenylacetyl)-2-pyrrolidinecarboxamide(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-(diphenylacetyl)-3-pyrrolidinoneO-methyloxime(2S)-2-[1-([1,1′-biphenyl]-4-ylcarbonyl)-4-methylene-2-pyrrolidinyl]-1H-benzimidazole(2S,4EZ)-N-allyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-(diphenylacetyl)-2-pyrrolidinecarboxamide(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N¹-pentyl-N²-(6-quinolinyl)-1,2-pyrrolidinedicarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(6-quinolinyl)-2-pyrrolidinecarboxamide(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-1-[4-(dimethylamino)butanoyl]-N-(6-quinolinyl)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N²-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N¹-(3-methoxyphenyl)-1,2-pyrrolidinedicarboxamide(2S,4EZ)-1-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-{[(4-methoxybenzyl)oxy]-imino}-2-pyrrolidinecarboxamide(2S)—N-(2-furylmethyl)-4-methylene-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-(diphenylacetyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-benzoyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quinolinyl)-2-pyrrolidinecarboxamide(2S,4EZ)-1-(4-cyanobenzoyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quinolinyl)-2-pyrrolidinecarboxamide(2S,4EZ)-N-(1,3-benzodioxol-5-ylmethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(3EZ,5S)-5-[(4-acetyl-1-piperazinyl)carbonyl]-1-acryloyl-3-pyrrolidinoneO-(3,4-dichlorobenzyl)oxime(2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-methylene-2-pyrrolidinecarboxamide(2S,4EZ)-4-(cyanomethylene)-N-(3,4-dimethoxybenzyl)-1-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(1-hydroxycyclohexyl)methyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1-hydroxycyclohexyl)methyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(2-naphthyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(3-hydroxypropyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-(3-hydroxypropyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-3-pyrrolidinoneO-methyloxime(3EZ,5S)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-1-[4-(4-pyridinyl)benzoyl]-3-pyrrolidinoneO-methyloxime(3EZ,5S)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-1-[4-(3-pyridinyl)benzoyl]-3-pyrrolidinoneO-methyloxime(3EZ,5S)-1-([1,1′-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy-4-phenyl-1-piperidinyl)carbonyl]-3-pyrrolidinoneO-methyloxime(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-benzyl-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-benzyl-N-(2-hydroxyethyl)-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-3-pyrrolidinoneO-methyloxime(3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-1-[4-(4-pyridinyl)benzoyl]-3-pyrrolidinoneO-methyloxime(3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-1-[4-(3-pyridinyl)benzoyl]-3-pyrrolidinoneO-methyloxime(3EZ,5S)-1-([1,1′-biphenyl]-4-ylsulfonyl)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-3-pyrrolidinoneO-methyloxime(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-(2-anilinoethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(4-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-(2-anilinoethyl)-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-1-piperidinyl)carbonyl]-3-pyrrolidinoneO-methyloxime(3EZ,5S)-1-([1,1′-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy-1-piperidinyl)carbonyl]-3-pyrrolidinoneO-methyloxime(2S,4EZ)-N-[(1S,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(4-hydroxybutyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-(4-hydroxybutyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1R,2S,3R,4S)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1R,2S)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4E and4Z)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4E and4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4E and4Z)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1R,2s)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(1S,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2RS)-3-({[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-carbonyl}amino)-2-hydroxypropanoicacid(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1RS)-2-hydroxy-1-methylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide4-({[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-carbonyl}amino)butanoicacid(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(2-naphthyl)ethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(1RS)-2-hydroxy-1-methylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(3EZ,5S)-5-[(4-hydroxy-1-piperidinyl)carbonyl]-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-3-pyrrolidinoneO-methyloxime(2S,4EZ)-N-[(1S,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-4-(methoxyimino)-1-[(2′-methyl[,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-(3-hydroxypropyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-(2-amino-2-oxoethyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(1S,2R,3S,4R)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(1R,2S,3R,4S)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-(trans-4-hydroxycyclohexyl)-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-1-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2R,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2R,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(2′-cyano[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′-cyano[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-(2-amino-2-oxoethyl)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-(3-amino-3-oxopropyl)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(2′-cyano[1′,1′-biphenyl]-4-yl)carbonyl]-N-[(1R,2R)-2-(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(3EZ,5S)-5-(3,4-dihydro-2(1H)-isoquinolinylcarbonyl)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-3-pyrrolidinoneO-methyloxime(2S,4EZ)-N-[(1R)-2-hydroxy-1-phenylethyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[(1R,2S)-2-hydroxy-1,2-diphenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2RS)-2-[({(2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]pyrrolidinyl}carbonyl)amino]-3-phenylpropanoicacid(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(1R,2S)-2-(aminocarbonyl)cyclohexyl]-1-[(2′,3-dimethyl[1′,1′-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide4′-{[(2S,4EZ)-2-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-4-(methoxyimino)pyrrolidinyl]carbonyl}[1,1′-biphenyl]-2-carbonitrile(3EZ,5S)-1-[(3′,4′-dichloro[1,1′-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinoneO-methyloxime(3EZ,5S)-1-[(2′,6′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinoneO-methyloxime(3EZ,5S)-1-[(2′,3-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonyl}-3-pyrrolidinoneO-methyloxime(3EZ,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-({4-[4-(trifluoromethyl)phenyl]-1-piperazinyl}carbonyl)-3-pyrrolidinoneO-methyloxime(3EZ,5S)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-5-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}carbonyl)-3-pyrrolidinoneO-methyloxime(2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1′,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-4-(methoxyimino)-N-methyl-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-4-(methoxyimino)-N,N-dimethyl-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(3R)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(3S)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(3R)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(3S)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-{[2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-{[2′-chloro[1,1′-biphenyl]-4-yl]carbonyl}-2-pyrrolidinecarboxamide(2S,4EZ)-N-(2-hydroxyphenyl)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[2-(hydroxymethyl)phenyl]-4-(methoxyimino)-1-[(2′-methyl[1,1-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide(2S,4E and4Z)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide(2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-phenylethyl)-2-pyrrolidinecarboxamide14. A pyrrolidine compound according to claim 1, selected from thefollowing group:(3EZ,5S)-5-(1H-benzimidazol-2-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinoneO-methyloxime(2S,4EZ)-N-(2,1,3-benzothiadiazol-4-yl)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxy-imino)-2-pyrrolidinecarboxamide(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(6-quinolinyl)-2-pyrrolidinecarboxamide.15. A pharmaceutical composition containing at least one pyrrolidinecompound according to claim 1 and a pharmaceutically acceptable carrier,diluent or excipient thereof.
 16. Process for the preparation of apyrrolidine compound according to claim 1, wherein the followingreaction is performed

whereby LG is a leaving group and the substituents R¹-R⁹, A and X are asabove defined.
 17. Process for the preparation of a pyrrolidine compoundaccording to claim 1, wherein the following reaction is performed:

whereby LG is a leaving group and the substituents R¹-R⁵, R¹¹, A, E, Q,X, Y and Z are as above defined.
 18. Process according to claim 17,wherein compound XV is obtained as follows:


19. A pyrrolidine compound according to claim 6, wherein R⁶ is H or CH₃.20. A method for treating and/or preventing premature labor, prematurebirth, and dysmenorrheal, comprising administering to a patient in needthereof an effective amount of a pharmaceutical composition according toclaim
 15. 21. The method according to claim 20 wherein thepharmaceutical composition is administered orally to the patient.
 22. Amethod for modulating the activity of the oxytocin receptor, comprisingadministering the pharmaceutical composition of claim 15 to a patient inneed thereof.
 23. The method according to claim 22, wherein modulatingthe activity of the oxytocin receptor blocks the oxytocin receptor orantagonizes the binding of oxytocin to its receptor.
 24. The methodaccording to claim 33, wherein the method is used for treating orpreventing disorders mediated by the oxytocin receptor.
 25. The methodaccording to claim 24, wherein the composition is administered orally tothe patient.